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Dwornik R, Białkowska K. Insights into genetic modifiers of breast cancer risk in carriers of BRCA1 and BRCA2 pathogenic variants. Hered Cancer Clin Pract 2025; 23:15. [PMID: 40296163 PMCID: PMC12036133 DOI: 10.1186/s13053-025-00313-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Accepted: 04/17/2025] [Indexed: 04/30/2025] Open
Abstract
Pathogenic variants in BRCA1 and BRCA2 are associated with an increased risk of developing several types of cancer, including breast cancer. However, the risk varies by other environmental and genetic factors present in carriers of mutation. To understand the value of these factors more clearly, a number of common genetic susceptibility variants have been studied through genome-wide association studies as potential genetic risk modifiers for BRCA1 and BRCA2 pathogenic variants carriers. Several studies have identified specific polymorphisms that may influence the risk of breast cancer development, either by increasing or reducing susceptibility. These variants are implicated in biological pathways such as DNA damage repair, hormonal regulation or cell proliferation. The identification and understanding of key genetic modifiers may provide valuable insights into development of personalized prevention, targeted therapies and screening strategies for high-risk individuals. This review presents the overview of known genetic risk modifiers for carriers of BRCA1 and BRCA2 pathogenic variants, their potential impact on risk, and their functional roles. Furthermore, it highlights the need for further research directions, including understanding the biological role of genetic modifiers in cancer development and the refinement of risk assessment models.
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Affiliation(s)
- Roksana Dwornik
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Katarzyna Białkowska
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
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2
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Tihagam RD, Lou S, Zhao Y, Liu KSY, Singh AT, Koo BI, Przanowski P, Li J, Huang X, Li H, Tushir-Singh J, Fejerman L, Bhatnagar S. The TRIM37 variant rs57141087 contributes to triple-negative breast cancer outcomes in Black women. EMBO Rep 2025; 26:245-272. [PMID: 39614126 PMCID: PMC11723928 DOI: 10.1038/s44319-024-00331-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 11/07/2024] [Accepted: 11/12/2024] [Indexed: 12/01/2024] Open
Abstract
Triple-negative breast cancer (TNBC) disproportionately affects younger Black women, who show more aggressive phenotypes and poorer outcomes than women of other racial identities. While the impact of socioenvironmental inequities within and beyond health systems is well documented, the genetic influence in TNBC-associated racial disparities remains elusive. Here, we report that cancer-free breast tissue from Black women expresses TRIM37 at a significantly higher level relative to White women. A reporter-based screen for regulatory variants identifies a non-coding risk variant rs57141087 in the 5' gene upstream region of the TRIM37 locus with enhancer activity. Mechanistically, rs57141087 increases enhancer-promoter interactions through NRF1, resulting in stronger TRIM37 promoter activity. Phenotypically, high TRIM37 levels drive neoplastic transformations in immortalized breast epithelial cells. Finally, context-dependent TRIM37 expression reveals that early-stage TRIM37 levels affect the initiation and trajectory of breast cancer progression. Together, our results indicate a genotype-informed association of oncogenic TRIM37 with TNBC risk in Black women and implicate TRIM37 as a predictive biomarker to better identify patients at risk of aggressive TNBC.
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Affiliation(s)
- Rachisan Djiake Tihagam
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, 95616, USA
| | - Song Lou
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, 95616, USA
| | - Yuanji Zhao
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, 95616, USA
| | - Kammi Song-Yan Liu
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, 95616, USA
| | - Arjun Tushir Singh
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, 95616, USA
- UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, 95817, USA
| | - Bon Il Koo
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, 95616, USA
| | - Piotr Przanowski
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Jie Li
- UC Davis Bioinformatics Core, University of California at Davis, Davis, CA, 95817, USA
| | - Xiaosong Huang
- Department of Public Health Sciences, University of California Davis, Davis, CA, 95817, USA
| | - Hong Li
- Department of Public Health Sciences, University of California Davis, Davis, CA, 95817, USA
| | - Jogender Tushir-Singh
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, 95616, USA
- UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, 95817, USA
| | - Laura Fejerman
- Department of Public Health Sciences, University of California Davis, Davis, CA, 95817, USA
| | - Sanchita Bhatnagar
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, 95616, USA.
- UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, 95817, USA.
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Chang YH, Head ST, Harrison T, Yu Y, Huff CD, Pasaniuc B, Lindström S, Bhattacharya A. Isoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.10.29.24316388. [PMID: 39574839 PMCID: PMC11581093 DOI: 10.1101/2024.10.29.24316388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2024]
Abstract
Integrating genome-wide association study (GWAS) and transcriptomic datasets can help identify potential mediators for germline genetic risk of cancer. However, traditional methods have been largely unsuccessful because of an overreliance on total gene expression. These approaches overlook alternative splicing, which can produce multiple isoforms from the same gene, each with potentially different effects on cancer risk. Here, we integrate genetic and multi-tissue isoform-level gene expression data from the Genotype Tissue-Expression Project (GTEx, N = 108-574) with publicly available European-ancestry GWAS summary statistics (all N > 20,000 cases) to identify both isoform- and gene-level risk associations with six cancers (breast, endometrial, colorectal, lung, ovarian, prostate) and six related cancer subtype classifications (N = 12 total). Compared to traditional methods leveraging total gene expression, directly modeling isoform expression through transcriptome-wide association studies (isoTWAS) substantially increases discovery of transcriptomic mechanisms underlying genetic associations. Using the same RNA-seq datasets, isoTWAS identified 164% more significant unique gene associations compared to TWAS (6,163 and 2,336, respectively), with isoTWAS-prioritized genes enriched 4-fold for evolutionarily-constrained genes (P = 6.1 × 10-13). isoTWAS tags transcriptomic associations at 52% more independent GWAS loci compared to TWAS across the six cancers. Additionally, isoform expression mediates an estimated 63% greater proportion of cancer risk SNP heritability compared to gene expression when evaluating cis-genetic influence on isoform expression. We highlight several notable isoTWAS associations that demonstrate GWAS colocalization at the isoform level but not at the gene level, including, CLPTM1L (lung cancer), LAMC1 (colorectal), and BABAM1 (breast). These results underscore the critical importance of modeling isoform-level expression to maximize discovery of genetic risk mechanisms for cancers.
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Affiliation(s)
- Yung-Han Chang
- Quantitative Sciences Program, The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA
| | - S. Taylor Head
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tabitha Harrison
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Yao Yu
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chad D. Huff
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bogdan Pasaniuc
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Sara Lindström
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Arjun Bhattacharya
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Institute for Data Science in Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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4
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McClellan JC, Li JL, Gao G, Huo D. Expression- and splicing-based multi-tissue transcriptome-wide association studies identified multiple genes for breast cancer by estrogen-receptor status. Breast Cancer Res 2024; 26:51. [PMID: 38515142 PMCID: PMC10958972 DOI: 10.1186/s13058-024-01809-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 03/14/2024] [Indexed: 03/23/2024] Open
Abstract
BACKGROUND Although several transcriptome-wide association studies (TWASs) have been performed to identify genes associated with overall breast cancer (BC) risk, only a few TWAS have explored the differences in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer. Additionally, these studies were based on gene expression prediction models trained primarily in breast tissue, and they did not account for alternative splicing of genes. METHODS In this study, we utilized two approaches to perform multi-tissue TWASs of breast cancer by ER subtype: (1) an expression-based TWAS that combined TWAS signals for each gene across multiple tissues and (2) a splicing-based TWAS that combined TWAS signals of all excised introns for each gene across tissues. To perform this TWAS, we utilized summary statistics for ER + BC from the Breast Cancer Association Consortium (BCAC) and for ER- BC from a meta-analysis of BCAC and the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). RESULTS In total, we identified 230 genes in 86 loci that were associated with ER + BC and 66 genes in 29 loci that were associated with ER- BC at a Bonferroni threshold of significance. Of these genes, 2 genes associated with ER + BC at the 1q21.1 locus were located at least 1 Mb from published GWAS hits. For several well-studied tumor suppressor genes such as TP53 and CHEK2 which have historically been thought to impact BC risk through rare, penetrant mutations, we discovered that common variants, which modulate gene expression, may additionally contribute to ER + or ER- etiology. CONCLUSIONS Our study comprehensively examined how differences in common variation contribute to molecular differences between ER + and ER- BC and introduces a novel, splicing-based framework that can be used in future TWAS studies.
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Affiliation(s)
- Julian C McClellan
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA
| | - James L Li
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA
| | - Guimin Gao
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA.
| | - Dezheng Huo
- Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA.
- Section of Hematology & Oncology, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA.
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5
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Barnes DR, Tyrer JP, Dennis J, Leslie G, Bolla MK, Lush M, Aeilts AM, Aittomäki K, Andrieu N, Andrulis IL, Anton-Culver H, Arason A, Arun BK, Balmaña J, Bandera EV, Barkardottir RB, Berger LP, de Gonzalez AB, Berthet P, Białkowska K, Bjørge L, Blanco AM, Blok MJ, Bobolis KA, Bogdanova NV, Brenton JD, Butz H, Buys SS, Caligo MA, Campbell I, Castillo C, Claes KB, Colonna SV, Cook LS, Daly MB, Dansonka-Mieszkowska A, de la Hoya M, deFazio A, DePersia A, Ding YC, Domchek SM, Dörk T, Einbeigi Z, Engel C, Evans DG, Foretova L, Fortner RT, Fostira F, Foti MC, Friedman E, Frone MN, Ganz PA, Gentry-Maharaj A, Glendon G, Godwin AK, González-Neira A, Greene MH, Gronwald J, Guerrieri-Gonzaga A, Hamann U, Hansen TV, Harris HR, Hauke J, Heitz F, Hogervorst FB, Hooning MJ, Hopper JL, Huff CD, Huntsman DG, Imyanitov EN, Izatt L, Jakubowska A, James PA, Janavicius R, John EM, Kar S, Karlan BY, Kennedy CJ, Kiemeney LA, Konstantopoulou I, Kupryjanczyk J, Laitman Y, Lavie O, Lawrenson K, Lester J, Lesueur F, Lopez-Pleguezuelos C, Mai PL, Manoukian S, May T, McNeish IA, Menon U, Milne RL, Modugno F, Mongiovi JM, Montagna M, Moysich KB, Neuhausen SL, Nielsen FC, Noguès C, et alBarnes DR, Tyrer JP, Dennis J, Leslie G, Bolla MK, Lush M, Aeilts AM, Aittomäki K, Andrieu N, Andrulis IL, Anton-Culver H, Arason A, Arun BK, Balmaña J, Bandera EV, Barkardottir RB, Berger LP, de Gonzalez AB, Berthet P, Białkowska K, Bjørge L, Blanco AM, Blok MJ, Bobolis KA, Bogdanova NV, Brenton JD, Butz H, Buys SS, Caligo MA, Campbell I, Castillo C, Claes KB, Colonna SV, Cook LS, Daly MB, Dansonka-Mieszkowska A, de la Hoya M, deFazio A, DePersia A, Ding YC, Domchek SM, Dörk T, Einbeigi Z, Engel C, Evans DG, Foretova L, Fortner RT, Fostira F, Foti MC, Friedman E, Frone MN, Ganz PA, Gentry-Maharaj A, Glendon G, Godwin AK, González-Neira A, Greene MH, Gronwald J, Guerrieri-Gonzaga A, Hamann U, Hansen TV, Harris HR, Hauke J, Heitz F, Hogervorst FB, Hooning MJ, Hopper JL, Huff CD, Huntsman DG, Imyanitov EN, Izatt L, Jakubowska A, James PA, Janavicius R, John EM, Kar S, Karlan BY, Kennedy CJ, Kiemeney LA, Konstantopoulou I, Kupryjanczyk J, Laitman Y, Lavie O, Lawrenson K, Lester J, Lesueur F, Lopez-Pleguezuelos C, Mai PL, Manoukian S, May T, McNeish IA, Menon U, Milne RL, Modugno F, Mongiovi JM, Montagna M, Moysich KB, Neuhausen SL, Nielsen FC, Noguès C, Oláh E, Olopade OI, Osorio A, Papi L, Pathak H, Pearce CL, Pedersen IS, Peixoto A, Pejovic T, Peng PC, Peshkin BN, Peterlongo P, Powell CB, Prokofyeva D, Pujana MA, Radice P, Rashid MU, Rennert G, Richenberg G, Sandler DP, Sasamoto N, Setiawan VW, Sharma P, Sieh W, Singer CF, Snape K, Sokolenko AP, Soucy P, Southey MC, Stoppa-Lyonnet D, Sutphen R, Sutter C, Teixeira MR, Terry KL, Thomsen LCV, Tischkowitz M, Toland AE, Van Gorp T, Vega A, Velez Edwards DR, Webb PM, Weitzel JN, Wentzensen N, Whittemore AS, Winham SJ, Wu AH, Yadav S, Yu Y, Ziogas A, Berchuck A, Couch FJ, Goode EL, Goodman MT, Monteiro AN, Offit K, Ramus SJ, Risch HA, Schildkraut JM, Thomassen M, Simard J, Easton DF, Jones MR, Chenevix-Trench G, Gayther SA, Antoniou AC, Pharoah PD. Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.02.29.24303243. [PMID: 38496424 PMCID: PMC10942532 DOI: 10.1101/2024.02.29.24303243] [Show More Authors] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Background Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. Results Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.
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Affiliation(s)
- Daniel R. Barnes
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Jonathan P. Tyrer
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Joe Dennis
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Goska Leslie
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Manjeet K. Bolla
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Michael Lush
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Amber M. Aeilts
- Department of Internal Medicine, Division of Human Genetics, The Ohio State University, Columbus, OH, USA
| | - Kristiina Aittomäki
- Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Nadine Andrieu
- Inserm U900, Paris, France
- Institut Curie, Paris, France
- Mines ParisTech, Fontainebleau, France
- PSL Research University, Paris, France
| | - Irene L. Andrulis
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
| | - Hoda Anton-Culver
- Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA
| | - Adalgeir Arason
- Department of Pathology, Landspitali - the National University Hospital of Iceland, Reykjavik, Iceland
- BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Banu K. Arun
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Judith Balmaña
- Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, University Hospital of Vall d’Hebron, Barcelona, Spain
| | - Elisa V. Bandera
- Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Rosa B. Barkardottir
- Department of Pathology, Landspitali - the National University Hospital of Iceland, Reykjavik, Iceland
- BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Lieke P.V. Berger
- University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, The Netherlands
| | | | - Pascaline Berthet
- Département de Biopathologie, Centre François Baclesse, Caen, France
| | - Katarzyna Białkowska
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Line Bjørge
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Amie M. Blanco
- Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA
| | - Marinus J. Blok
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Kristie A. Bobolis
- City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA
| | - Natalia V. Bogdanova
- Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
- N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
| | - James D. Brenton
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Henriett Butz
- Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
- National Tumour Biology Laboratory, National Institute of Oncology, Budapest, Hungary
- Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary
| | - Saundra S. Buys
- Department of Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT, USA
| | | | - Ian Campbell
- Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Carmen Castillo
- Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain
| | - Kathleen B.M. Claes
- Centre for Medical Genetics, Ghent University, Gent, Belgium
- Department of Biomolecular Medicine, University of Ghent, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | | | - EMBRACE Collaborators
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Sarah V. Colonna
- Department of Internal Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT, USA
| | - Linda S. Cook
- Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO, USA
| | - Mary B. Daly
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Agnieszka Dansonka-Mieszkowska
- Department of Pathology and Laboratory Medicine, Institute of Oncology and Maria Sklodowska-Curie Cancer Center, Warsaw, Poland
| | - Miguel de la Hoya
- Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain
| | - Anna deFazio
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, New South Wales, Australia
| | - Allison DePersia
- Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA
- The University of Chicago Pritzker School of Medicine, Chicago, IL, USA
| | - Yuan Chun Ding
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Susan M. Domchek
- Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Zakaria Einbeigi
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Christoph Engel
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
| | - D. Gareth Evans
- Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary’s Hospital, Manchester, UK
- Genomic Medicine, North West Genomics hub, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary’s Hospital, Manchester, UK
| | - Lenka Foretova
- Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Renée T. Fortner
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway
| | - Florentia Fostira
- Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research ‘Demokritos’, Athens, Greece
| | | | - Eitan Friedman
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
- The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel
- Assuta Medical Center, Tel-Aviv, Israel
| | - Megan N. Frone
- National Cancer Institute, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA
| | - Patricia A. Ganz
- Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, CA, USA
| | - Aleksandra Gentry-Maharaj
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK
| | - Gord Glendon
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
| | - Andrew K. Godwin
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Anna González-Neira
- Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre, Madrid, Spain
- Spanish Network on Rare Diseases, Madrid, Spain
| | - Mark H. Greene
- National Cancer Institute, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA
| | - Jacek Gronwald
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Aliana Guerrieri-Gonzaga
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Ute Hamann
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Thomas v.O. Hansen
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Holly R. Harris
- Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Jan Hauke
- Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Florian Heitz
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany
| | - Frans B.L. Hogervorst
- Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
| | - Maartje J. Hooning
- Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - John L. Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Chad D Huff
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David G. Huntsman
- British Columbia’s Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
- Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
- Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada
| | - Evgeny N. Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg, Russia
| | - kConFab Investigators
- Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - Louise Izatt
- Clinical Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
| | - Anna Jakubowska
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
- Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland
| | - Paul A. James
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Center and the Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Ramunas Janavicius
- State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
- Hematology, Oncology and Transfusion Medicine Center, Oncogenetics Unit, Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania
- Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Esther M. John
- Department of Epidemiology & Population Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, USA
- Department of Medicine (Oncology), Stanford University School of Medicine, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford University, Stanford, CA, USA
| | - Siddhartha Kar
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Beth Y. Karlan
- David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA
- Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Catherine J. Kennedy
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | | | - Irene Konstantopoulou
- Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research ‘Demokritos’, Athens, Greece
| | - Jolanta Kupryjanczyk
- Department of Pathology and Laboratory Medicine, Institute of Oncology and Maria Sklodowska-Curie Cancer Center, Warsaw, Poland
| | - Yael Laitman
- The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Ofer Lavie
- Technion-Israel Institute of Technology, Haifa, Israel
- Carmel Medical Center, Haifa, Israel
| | - Kate Lawrenson
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Women’s Cancer Program at the Samuel Oschin Cancer Institute Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jenny Lester
- David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA
- Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Fabienne Lesueur
- Inserm U900, Paris, France
- Institut Curie, Paris, France
- Mines ParisTech, Fontainebleau, France
- PSL Research University, Paris, France
| | - Carlos Lopez-Pleguezuelos
- Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
- Escola de Doutoramento Internacional, Universidade de Santiago, Santiago de Compostela, Spain
| | - Phuong L. Mai
- Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Siranoush Manoukian
- Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Taymaa May
- Princess Margaret Cancer Center, Toronto, Canada
| | - Iain A. McNeish
- Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery & Cancer, Imperial College London, London, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Usha Menon
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK
| | - Roger L. Milne
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Francesmary Modugno
- Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA
- Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jennifer M. Mongiovi
- Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Marco Montagna
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | | | - Susan L. Neuhausen
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Finn C. Nielsen
- Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Catherine Noguès
- Département d’Anticipation et de Suivi des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France
- Aix Marseille Université, INSERM, IRD, SESSTIM, Marseille, France
| | - Edit Oláh
- Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
| | | | - Ana Osorio
- Spanish Network on Rare Diseases, Madrid, Spain
- Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Madrid, Spain
| | - Laura Papi
- Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, Medical Genetics Unit, University of Florence, Florence, Italy
| | - Harsh Pathak
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Celeste L. Pearce
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Inge S. Pedersen
- Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark
- Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Ana Peixoto
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal
| | - Tanja Pejovic
- Department of Obstetrics & Gynecology, Providence Medical Center, Medford, OR, USA
- Providence Cancer Center, Medford, OR, USA
| | - Pei-Chen Peng
- Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Beth N. Peshkin
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
- Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research, Georgetown University, Washington, DC, USA
| | - Paolo Peterlongo
- Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy
| | - C. Bethan Powell
- Hereditary Cancer Program, Kaiser Permanente Northern California, San Francisco, CA, USA
| | | | - Miquel Angel Pujana
- ProCURE, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain
- ProCURE, IDIBGI (Girona Biomedical Research Institute), Catalan Institute of Oncology, Girona, Spain
| | - Paolo Radice
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
| | - Muhammad U. Rashid
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan
| | - Gad Rennert
- Technion-Israel Institute of Technology, Haifa, Israel
- The Association for Promotion of Research in Precision Medicine, Haifa, Israel
| | - George Richenberg
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Dale P. Sandler
- Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Rockville, MD, USA
| | - Naoko Sasamoto
- Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, MA, USA
- Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA
| | - Veronica W. Setiawan
- Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA
| | - Priyanka Sharma
- Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA
| | - Weiva Sieh
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Christian F. Singer
- Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Katie Snape
- Medical Genetics Unit, St George’s, University of London, London, UK
| | - Anna P. Sokolenko
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg, Russia
| | - Penny Soucy
- Genomics Center, Centre Hospitalier Universitaire de Québec – Université Laval Research Center, Québec City, QC, Canada
| | - Melissa C. Southey
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
- Department of Clinical Pathology, Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, Victoria, Australia
| | - Dominique Stoppa-Lyonnet
- Genetics Department, Institut Curie, Paris, France
- Unité INSERM U830, Paris, France
- Université Paris Cité, Paris, France
| | - Rebecca Sutphen
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Christian Sutter
- Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
| | - Manuel R. Teixeira
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal
- Department of Pathology and Molecular Immunology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
| | - Kathryn L. Terry
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Obstetrics and Gynecology Epidemiology Center, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Liv Cecilie V. Thomsen
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway
- Medical Birth Registry of Norway, Norwegian Institute of Public Health, Norway
| | - Marc Tischkowitz
- Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Amanda E. Toland
- Department of Internal Medicine, Division of Human Genetics, The Ohio State University, Columbus, OH, USA
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
| | - Toon Van Gorp
- Division of Gynecologic Oncology, University Hospital Leuven, Leuven, Belgium
- Leuven Cancer Institute, University of Leuven, Leuven, Belgium
| | - Ana Vega
- Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
- Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | - Digna R. Velez Edwards
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Penelope M. Webb
- Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | | | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Alice S. Whittemore
- Department of Epidemiology & Population Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA
| | - Stacey J. Winham
- Department of Quantitative Health Sciences, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Anna H. Wu
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Yao Yu
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Argyrios Ziogas
- Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA
| | - Andrew Berchuck
- Department of Gynecologic Oncology, Duke University Hospital, Durham, NC, USA
| | - Fergus J. Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Ellen L. Goode
- Department of Quantitative Health Sciences, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Marc T. Goodman
- Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Alvaro N. Monteiro
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Kenneth Offit
- Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- AnaNeo Therapeutics, New York, NY, USA
| | - Susan J. Ramus
- School of Clinical Medicine, Faculty of Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia
- Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia
| | - Harvey A. Risch
- Chronic Disease Epidemiology, Yale School of Medicine, New Haven, CT, USA
| | | | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
- Clinical Genome Center, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Jacques Simard
- Genomics Center, Centre Hospitalier Universitaire de Québec – Université Laval Research Center, Québec City, QC, Canada
- Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada
| | - Douglas F. Easton
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Michelle R. Jones
- Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Georgia Chenevix-Trench
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Simon A. Gayther
- Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Antonis C. Antoniou
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Paul D.P. Pharoah
- Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Hartkopf AD, Fehm TN, Welslau M, Müller V, Schütz F, Fasching PA, Janni W, Witzel I, Thomssen C, Beierlein M, Belleville E, Untch M, Thill M, Tesch H, Ditsch N, Lux MP, Aktas B, Banys-Paluchowski M, Kolberg-Liedtke C, Wöckel A, Kolberg HC, Harbeck N, Stickeler E, Bartsch R, Schneeweiss A, Ettl J, Würstlein R, Krug D, Taran FA, Lüftner D. Update Breast Cancer 2023 Part 1 - Early Stage Breast Cancer. Geburtshilfe Frauenheilkd 2023; 83:653-663. [PMID: 37916183 PMCID: PMC10617391 DOI: 10.1055/a-2074-0551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 11/03/2023] Open
Abstract
With abemaciclib (monarchE study) and olaparib (OlympiA study) gaining approval in the adjuvant treatment setting, a significant change in the standard of care for patients with early stage breast cancer has been established for some time now. Accordingly, some diverse developments are slowly being transferred from the metastatic to the adjuvant treatment setting. Recently, there have also been positive reports of the NATALEE study. Other clinical studies are currently investigating substances that are already established in the metastatic setting. These include, for example, the DESTINY Breast05 study with trastuzumab deruxtecan and the SASCIA study with sacituzumab govitecan. In this review paper, we summarize and place in context the latest developments over the past months.
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Affiliation(s)
- Andreas D. Hartkopf
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Tanja N. Fehm
- Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany
| | | | - Volkmar Müller
- Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany
| | - Florian Schütz
- Gynäkologie und Geburtshilfe, Diakonissen-Stiftungs-Krankenhaus Speyer, Speyer, Germany
| | - Peter A. Fasching
- Erlangen University Hospital, Department of Gynecology and Obstetrics; Comprehensive Cancer Center Erlangen EMN, Friedrich-Alexander University Erlangen-Nuremberg,
Erlangen, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Isabell Witzel
- Klinik für Gynäkologie, Universitätsspital Zürich, Zürich, Switzerland
| | - Christoph Thomssen
- Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Milena Beierlein
- Erlangen University Hospital, Department of Gynecology and Obstetrics; Comprehensive Cancer Center Erlangen EMN, Friedrich-Alexander University Erlangen-Nuremberg,
Erlangen, Germany
| | | | - Michael Untch
- Clinic for Gynecology and Obstetrics, Breast Cancer Center, Gynecologic Oncology Center, Helios Klinikum Berlin Buch, Berlin, Germany
| | - Marc Thill
- Department of Gynecology and Gynecological Oncology, Agaplesion Markus Krankenhaus, Frankfurt am Main, Germany
| | - Hans Tesch
- Oncology Practice at Bethanien Hospital, Frankfurt am Main, Germany
| | - Nina Ditsch
- Department of Gynecology and Obstetrics, University Hospital Augsburg, Augsburg, Germany
| | - Michael P. Lux
- Klinik für Gynäkologie und Geburtshilfe, Frauenklinik St. Louise, Paderborn, St. Josefs-Krankenhaus, Salzkotten, St. Vincenz Krankenhaus GmbH, Paderborn, Germany
| | - Bahriye Aktas
- Department of Gynecology, University of Leipzig Medical Center, Leipzig, Germany
| | - Maggie Banys-Paluchowski
- Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | | | - Achim Wöckel
- Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
| | | | - Nadia Harbeck
- Breast Center, Department of Gynecology and Obstetrics and CCC Munich LMU, LMU University Hospital, München, Germany
| | - Elmar Stickeler
- Department of Obstetrics and Gynecology, Center for Integrated Oncology (CIO Aachen, Bonn, Cologne, Düsseldorf), University Hospital of RWTH Aachen, Aachen, Germany
| | - Rupert Bartsch
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Andreas Schneeweiss
- National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Johannes Ettl
- Klinik für Frauenheilkunde und Gynäkologie, Klinikum Kempten, Klinikverbund Allgäu, Kempten, Germany
| | - Rachel Würstlein
- Breast Center, Department of Gynecology and Obstetrics and CCC Munich LMU, LMU University Hospital, München, Germany
| | - David Krug
- Klinik für Strahlentherapie, Universitätsklinkum Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Florin-Andrei Taran
- Department of Gynecology and Obstetrics, University Hospital Freiburg, Freiburg, Germany
| | - Diana Lüftner
- Medical University of Brandenburg Theodor-Fontane, Immanuel Hospital Märkische Schweiz, Buckow, Germany
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Jiang H, Kong N, Liu Z, West SC, Chan YW. Human Endonuclease ANKLE1 Localizes at the Midbody and Processes Chromatin Bridges to Prevent DNA Damage and cGAS-STING Activation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2204388. [PMID: 36825683 PMCID: PMC10131833 DOI: 10.1002/advs.202204388] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/12/2022] [Indexed: 06/18/2023]
Abstract
Chromatin bridges connecting the two segregating daughter nuclei arise from chromosome fusion or unresolved interchromosomal linkage. Persistent chromatin bridges are trapped in the cleavage plane, triggering cytokinesis delay. The trapped bridges occasionally break during cytokinesis, inducing DNA damage and chromosomal rearrangements. Recently, Caenorhabditis elegans LEM-3 and human TREX1 nucleases have been shown to process chromatin bridges. Here, it is shown that ANKLE1 endonuclease, the human ortholog of LEM-3, accumulates at the bulge-like structure of the midbody via its N-terminal ankyrin repeats. Importantly, ANKLE1-/- knockout cells display an elevated level of G1-specific 53BP1 nuclear bodies, prolonged activation of the DNA damage response, and replication stress. Increased DNA damage observed in ANKLE1-/- cells is rescued by inhibiting actin polymerization or reducing actomyosin contractility. ANKLE1 does not act in conjunction with structure-selective endonucleases, GEN1 and MUS81 in resolving recombination intermediates. Instead, ANKLE1 acts on chromatin bridges by priming TREX1 nucleolytic activity and cleaving bridge DNA to prevent the formation of micronuclei and cytosolic dsDNA that activate the cGAS-STING pathway. It is therefore proposed that ANKLE1 prevents DNA damage and autoimmunity by cleaving chromatin bridges to avoid catastrophic breakage mediated by actomyosin contractile forces.
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Affiliation(s)
- Huadong Jiang
- School of Biological SciencesThe University of Hong KongPokfulamHong Kong
| | - Nannan Kong
- School of Biological SciencesThe University of Hong KongPokfulamHong Kong
| | - Zeyuan Liu
- School of Biological SciencesThe University of Hong KongPokfulamHong Kong
| | - Stephen C. West
- The Francis Crick InstituteDNA Recombination and Repair Laboratory1 Midland RoadLondonNW1 1ATUK
| | - Ying Wai Chan
- School of Biological SciencesThe University of Hong KongPokfulamHong Kong
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8
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Przanowski P, Przanowska RK, Guertin MJ. ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation. Commun Biol 2023; 6:231. [PMID: 36859531 PMCID: PMC9977882 DOI: 10.1038/s42003-023-04611-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 02/20/2023] [Indexed: 03/03/2023] Open
Abstract
Alleles within the chr19p13.1 locus are associated with increased risk of both ovarian and breast cancer and increased expression of the ANKLE1 gene. ANKLE1 is molecularly characterized as an endonuclease that efficiently cuts branched DNA and shuttles between the nucleus and cytoplasm. However, the role of ANKLE1 in mammalian development and homeostasis remains unknown. In normal development ANKLE1 expression is limited to the erythroblast lineage and we found that ANKLE1's role is to cleave the mitochondrial genome during erythropoiesis. We show that ectopic expression of ANKLE1 in breast epithelial-derived cells leads to genome instability and mitochondrial DNA (mtDNA) cleavage. mtDNA degradation then leads to mitophagy and causes a shift from oxidative phosphorylation to glycolysis (Warburg effect). Moreover, mtDNA degradation activates STAT1 and expression of epithelial-mesenchymal transition (EMT) genes. Reduction in mitochondrial content contributes to apoptosis resistance, which may allow precancerous cells to avoid apoptotic checkpoints and proliferate. These findings provide evidence that ANKLE1 is the causal cancer susceptibility gene in the chr19p13.1 locus and describe mechanisms by which higher ANKLE1 expression promotes cancer risk.
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Affiliation(s)
- Piotr Przanowski
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA.
- Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, VA, USA.
| | - Róża K Przanowska
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Michael J Guertin
- Center for Cell Analysis and Modeling, University of Connecticut, Farmington, CT, USA.
- Department of Genetics and Genome Sciences, University of Connecticut, Farmington, CT, USA.
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9
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Ding YC, Adamson AW, Bakhtiari M, Patrick C, Park J, Laitman Y, Weitzel JN, Bafna V, Friedman E, Neuhausen SL. Variable number tandem repeats (VNTRs) as modifiers of breast cancer risk in carriers of BRCA1 185delAG. Eur J Hum Genet 2023; 31:216-222. [PMID: 36434258 PMCID: PMC9905572 DOI: 10.1038/s41431-022-01238-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 10/10/2022] [Accepted: 11/08/2022] [Indexed: 11/27/2022] Open
Abstract
Despite substantial efforts in identifying both rare and common variants affecting disease risk, in the majority of diseases, a large proportion of unexplained genetic risk remains. We propose that variable number tandem repeats (VNTRs) may explain a proportion of the missing genetic risk. Herein, in a pilot study with a retrospective cohort design, we tested whether VNTRs are causal modifiers of breast cancer risk in 347 female carriers of the BRCA1 185delAG pathogenic variant, an important group given their high risk of developing breast cancer. We performed targeted-capture to sequence VNTRs, called genotypes with adVNTR, tested the association of VNTRs and breast cancer risk using Cox regression models, and estimated the effect size using a retrospective likelihood approach. Of 303 VNTRs that passed quality control checks, 4 VNTRs were significantly associated with risk to develop breast cancer at false discovery rate [FDR] < 0.05 and an additional 4 VNTRs had FDR < 0.25. After determining the specific risk alleles, there was a significantly earlier age at diagnosis of breast cancer in carriers of the risk alleles compared to those without the risk alleles for seven of eight VNTRs. One example is a VNTR in exon 2 of LINC01973 with a per-allele hazard ratio of 1.58 (1.07-2.33) and 5.28 (2.79-9.99) for the homozygous risk-allele genotype. Results from this first systematic study of VNTRs demonstrate that VNTRs may explain a proportion of the unexplained genetic risk for breast cancer.
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Affiliation(s)
- Yuan Chun Ding
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Aaron W Adamson
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Mehrdad Bakhtiari
- Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA
| | - Carmina Patrick
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Jonghun Park
- Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA
| | - Yael Laitman
- Oncogenetics Unit, Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel
| | - Jeffrey N Weitzel
- Latin American School of Oncology, Tuxla Gutierrez, Chiapas, MX and Natera, San Carlos, CA, USA
| | - Vineet Bafna
- Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA
| | - Eitan Friedman
- Oncogenetics Unit, Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel
- The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- The Center for Preventive Personalized Medicine, Assuta Medical Center, Tel Aviv, Israel
| | - Susan L Neuhausen
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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10
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Hu J, Huang J, Liu X, Liu X. Response Best-subset Selector for Multivariate Regression with High-dimensional Response Variables. Biometrika 2022. [DOI: 10.1093/biomet/asac037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Summary
This article investigates the statistical problem of response-variable selection with high-dimensional response variables and a diverging number of predictor variables with respect to the sample size in the framework of multivariate linear regression. A response best-subset selection model is proposed by introducing a 0–1 selection indictor for each response variable, then a response best-subset selector is developed by introducing a separation parameter and a novel penalized least-squares function. The developed procedure can perform response-variable selection and regression-coefficient estimation simultaneously, and the proposed response best-subset selector has model consistency under mild conditions for both fixed and diverging numbers of predictor variables. Also, consistency and asymptotic normality of regression-coefficient estimators are presented for cases with a fixed dimension, and it is discovered that the Bonferroni test is a special response best-subset selector. Finite-sample simulations show that the response best-subset selector has strong advantages over existing competitors in terms of the Matthews correlation coefficient, a criterion aimed at balancing accuracies for both true and false response variables. An analysis of actual data demonstrates the effectiveness of the response best-subset selector in an application involving the identification of dosage-sensitive genes.
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Affiliation(s)
- Jianhua Hu
- Shanghai University of Finance and Economics School of Statistics and Management, , Shanghai 200433, China
| | - Jian Huang
- University of Iowa Department of Statistics and Actuarial Science, , Iowa, U.S.A
| | - Xiaoqian Liu
- York University Department of Mathematics and Statistics, , Toronto, Ontario M3J 1P3, Canada
| | - Xu Liu
- Shanghai University of Finance and Economics School of Statistics and Management, , Shanghai 200433, China
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11
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Zhu Q, Wang J, Yu H, Hu Q, Bateman NW, Long M, Rosario S, Schultz E, Dalgard CL, Wilkerson MD, Sukumar G, Huang RY, Kaur J, Lele SB, Zsiros E, Villella J, Lugade A, Moysich K, Conrads TP, Maxwell GL, Odunsi K. Whole-Genome Sequencing Identifies PPARGC1A as a Putative Modifier of Cancer Risk in BRCA1/2 Mutation Carriers. Cancers (Basel) 2022; 14:2350. [PMID: 35625955 PMCID: PMC9139302 DOI: 10.3390/cancers14102350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/03/2022] [Accepted: 05/06/2022] [Indexed: 02/01/2023] Open
Abstract
While BRCA1 and BRCA2 mutations are known to confer the largest risk of breast cancer and ovarian cancer, the incomplete penetrance of the mutations and the substantial variability in age at cancer onset among carriers suggest additional factors modifying the risk of cancer in BRCA1/2 mutation carriers. To identify genetic modifiers of BRCA1/2, we carried out a whole-genome sequencing study of 66 ovarian cancer patients that were enriched with BRCA carriers, followed by validation using data from the Pan-Cancer Analysis of Whole Genomes Consortium. We found PPARGC1A, a master regulator of mitochondrial biogenesis and function, to be highly mutated in BRCA carriers, and patients with both PPARGC1A and BRCA1/2 mutations were diagnosed with breast or ovarian cancer at significantly younger ages, while the mutation status of each gene alone did not significantly associate with age of onset. Our study suggests PPARGC1A as a possible BRCA modifier gene. Upon further validation, this finding can help improve cancer risk prediction and provide personalized preventive care for BRCA carriers.
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Affiliation(s)
- Qianqian Zhu
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.W.); (H.Y.); (Q.H.); (M.L.); (S.R.); (E.S.)
| | - Jie Wang
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.W.); (H.Y.); (Q.H.); (M.L.); (S.R.); (E.S.)
| | - Han Yu
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.W.); (H.Y.); (Q.H.); (M.L.); (S.R.); (E.S.)
| | - Qiang Hu
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.W.); (H.Y.); (Q.H.); (M.L.); (S.R.); (E.S.)
| | - Nicholas W. Bateman
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA; (N.W.B.); (T.P.C.); (G.L.M.)
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Dr., Suite 100, Bethesda, MD 20817, USA;
| | - Mark Long
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.W.); (H.Y.); (Q.H.); (M.L.); (S.R.); (E.S.)
| | - Spencer Rosario
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.W.); (H.Y.); (Q.H.); (M.L.); (S.R.); (E.S.)
| | - Emily Schultz
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.W.); (H.Y.); (Q.H.); (M.L.); (S.R.); (E.S.)
| | - Clifton L. Dalgard
- The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (C.L.D.); (M.D.W.)
- Department of Anatomy Physiology and Genetics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
| | - Matthew D. Wilkerson
- The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (C.L.D.); (M.D.W.)
- Department of Anatomy Physiology and Genetics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
| | - Gauthaman Sukumar
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Dr., Suite 100, Bethesda, MD 20817, USA;
- Department of Anatomy Physiology and Genetics, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
| | - Ruea-Yea Huang
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (R.-Y.H.); (A.L.)
| | - Jasmine Kaur
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.K.); (S.B.L.); (E.Z.)
| | - Shashikant B. Lele
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.K.); (S.B.L.); (E.Z.)
| | - Emese Zsiros
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.K.); (S.B.L.); (E.Z.)
| | - Jeannine Villella
- Division of Gynecologic Oncology, Lenox Hill Hospital/Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, NY 11549, USA;
| | - Amit Lugade
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (R.-Y.H.); (A.L.)
| | - Kirsten Moysich
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Thomas P. Conrads
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA; (N.W.B.); (T.P.C.); (G.L.M.)
- Women’s Health Integrated Research Center, Women’s Service Line, Inova Health System, 3289 Woodburn Rd, Annandale, VA 22003, USA
| | - George L. Maxwell
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA; (N.W.B.); (T.P.C.); (G.L.M.)
- Women’s Health Integrated Research Center, Women’s Service Line, Inova Health System, 3289 Woodburn Rd, Annandale, VA 22003, USA
| | - Kunle Odunsi
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (R.-Y.H.); (A.L.)
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (J.K.); (S.B.L.); (E.Z.)
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL 60637, USA
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12
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Heyliger SO, Soliman KFA, Saulsbury MD, Reams RR. Prognostic Relevance of ZNF844 and Chr 19p13.2 KRAB-Zinc Finger Proteins in Clear Cell Renal Carcinoma. Cancer Genomics Proteomics 2022; 19:305-327. [PMID: 35430565 DOI: 10.21873/cgp.20322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/05/2022] [Accepted: 02/11/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND/AIM Clear-cell renal cell carcinoma (ccRCC) is the most common and aggressive form of all urological cancers, with poor prognosis and high mortality. Despite growing evidence of involvement in carcinogenesis, the role of KRAB-ZFP in ccRCC has not been fully explored. KRAB Zinc finger proteins (KRAB-ZFPs) are the largest family of mammalian transcription regulators. They are differentially expressed in various tissues during cellular development and phenotypic differentiation. MATERIALS AND METHODS In this study, the levels of transcripts of ccRCC from The Cancer Genome Atlas (TCGA) dataset were used to identify prognostic biomarkers in this disease. RESULTS Using bioinformatics techniques, we demonstrate that approximately 60% of KRAB zinc finger proteins located on chromosome 19p13.2 are differentially expressed, with all but two being down-regulated in ccRCC. Moreover, ZNF844, a paralog of ZNF433, was the most down-regulated across all histological grades and pathological stages (p<0.001). In addition, the decrease in ZNF844 expression was associated with poor patient survival (HR=0.41; 95% CI=0.3-0.56; p<0.0001). Gene Set Enrichment Analysis of genes inversely co-expressed with ZNF844 revealed that enriched pathways were consistently related to immune and translation processes (p<0.05, FDR <0.05). Lastly, ZNF844 expression showed moderate, inverse correlation to Helper T-cell (CD4 or Th1) subtype 1 (R=-0.558, p=5.15×10-39) infiltration and with the exhausted T-cell phenotype (R=-0.37; p=4.1×10-21). CONCLUSION Down-regulation of KRAB-ZFPs at 19p13.2 may represent a signature for ccRCC. Moreover, ZNF844 is a prognostic marker for ccRCC and may serve as a putative immune-related tumor suppressor gene.
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Affiliation(s)
- Simone O Heyliger
- Department of Pharmaceutical Sciences, Hampton University, Hampton, VA, U.S.A
| | - Karam F A Soliman
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A
| | - Marilyn D Saulsbury
- Department of Pharmaceutical Sciences, Hampton University, Hampton, VA, U.S.A
| | - R Renee Reams
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.
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13
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Ezeome ER, Yawe KDT, Ayandipo O, Badejo O, Adebamowo SN, Achusi B, Fowotade A, Ogun G, Adebamowo CA. The African Female Breast Cancer Epidemiology Study Protocol. Front Oncol 2022; 12:856182. [PMID: 35494056 PMCID: PMC9044037 DOI: 10.3389/fonc.2022.856182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/08/2022] [Indexed: 11/21/2022] Open
Abstract
Breast cancer is now the commonest cancer in most sub-Saharan African countries. Few studies of the epidemiology and genomics of breast cancer and its molecular subtypes in these countries have been done. The African Female Breast Cancer Epidemiology (AFBRECANE) study, a part of the Human Heredity and Health in Africa (H3Africa) initiative, is designed to study the genomics and epidemiology of breast cancer and its molecular subtypes in Nigerian women. We link recruitment of breast cancer cases at study sites with population-based cancer registries activities to enable ascertainment of the incidence of breast cancer and its molecular subtypes. We use centralized laboratory processing to characterize the histopathological and molecular diagnosis of breast cancer and its subtypes using multiple technologies. By combining genome-wide association study (GWAS) data from this study with that generated from 12,000 women participating in our prospective cohort study of cervical cancer, we conduct GWAS of breast cancer in an entirely indigenous African population. We test associations between dietary intakes and breast cancer and focus on vitamin D which we measure using dietary intakes, serum vitamin D, and Mendelian randomization. This paper describes the AFBRECANE project, its design, objectives and anticipated contributions to knowledge and understanding of breast cancer.
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Affiliation(s)
- Emmanuel R. Ezeome
- Department of Surgery, College of Medicine, University of Nigeria, Enugu, Nigeria
- Oncology Center, University of Nigeria Teaching Hospital, Enugu, Nigeria
| | - King-David T. Yawe
- Department of Surgery, University of Abuja Teaching Hospital, Abuja, Nigeria
| | | | - Olawale Badejo
- Department of Pathology, National Hospital, Abuja, Nigeria
| | - Sally N. Adebamowo
- Department of Epidemiology and Public Health, and Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Benerdin Achusi
- Department of Anatomic Pathology, Federal Medical Center, Abuja, Nigeria
| | - Adeola Fowotade
- Department of Medical Microbiology, University College Hospital, Ibadan, Nigeria
| | - Gabriel Ogun
- Department of Pathology, University College Hospital, Ibadan, Nigeria
| | | | - Clement A. Adebamowo
- Department of Epidemiology and Public Health, and Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States
- Institute of Human Virology Nigeria, Abuja, Nigeria
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14
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Penninckx S, Pariset E, Cekanaviciute E, Costes SV. Quantification of radiation-induced DNA double strand break repair foci to evaluate and predict biological responses to ionizing radiation. NAR Cancer 2021; 3:zcab046. [PMID: 35692378 PMCID: PMC8693576 DOI: 10.1093/narcan/zcab046] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/08/2021] [Accepted: 12/17/2021] [Indexed: 08/08/2023] Open
Abstract
Radiation-induced foci (RIF) are nuclear puncta visualized by immunostaining of proteins that regulate DNA double-strand break (DSB) repair after exposure to ionizing radiation. RIF are a standard metric for measuring DSB formation and repair in clinical, environmental and space radiobiology. The time course and dose dependence of their formation has great potential to predict in vivo responses to ionizing radiation, predisposition to cancer and probability of adverse reactions to radiotherapy. However, increasing complexity of experimentally and therapeutically setups (charged particle, FLASH …) is associated with several confounding factors that must be taken into account when interpreting RIF values. In this review, we discuss the spatiotemporal characteristics of RIF development after irradiation, addressing the common confounding factors, including cell proliferation and foci merging. We also describe the relevant endpoints and mathematical models that enable accurate biological interpretation of RIF formation and resolution. Finally, we discuss the use of RIF as a biomarker for quantification and prediction of in vivo radiation responses, including important caveats relating to the choice of the biological endpoint and the detection method. This review intends to help scientific community design radiobiology experiments using RIF as a key metric and to provide suggestions for their biological interpretation.
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Affiliation(s)
- Sébastien Penninckx
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
- Medical Physics Department, Jules Bordet Institute, Université Libre de Bruxelles, 1 Rue Héger-Bordet, 1000 Brussels, Belgium
| | - Eloise Pariset
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
- Universities Space Research Association, 615 National Avenue, Mountain View, CA 94043, USA
| | - Egle Cekanaviciute
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Sylvain V Costes
- To whom correspondence should be addressed. Tel: +1 650 604 5343;
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15
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Ruiz de Garibay G, Fernandez-Garcia I, Mazoyer S, Leme de Calais F, Ameri P, Vijayakumar S, Martinez-Ruiz H, Damiola F, Barjhoux L, Thomassen M, Andersen LVB, Herranz C, Mateo F, Palomero L, Espín R, Gómez A, García N, Jimenez D, Bonifaci N, Extremera AI, Castaño J, Raya A, Eyras E, Puente XS, Brunet J, Lázaro C, Radice P, Barnes DR, Antoniou AC, Spurdle AB, de la Hoya M, Baralle D, Barcellos-Hoff MH, Pujana MA. Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants. Hum Mutat 2021; 42:1488-1502. [PMID: 34420246 DOI: 10.1002/humu.24276] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 08/11/2021] [Accepted: 08/18/2021] [Indexed: 11/12/2022]
Abstract
Germline pathogenic variants in BRCA1 confer a high risk of developing breast and ovarian cancer. The BRCA1 exon 11 (formally exon 10) is one of the largest exons and codes for the nuclear localization signals of the corresponding gene product. This exon can be partially or entirely skipped during pre-mRNA splicing, leading to three major in-frame isoforms that are detectable in most cell types and tissue, and in normal and cancer settings. However, it is unclear whether the splicing imbalance of this exon is associated with cancer risk. Here we identify a common genetic variant in intron 10, rs5820483 (NC_000017.11:g.43095106_43095108dup), which is associated with exon 11 isoform expression and alternative splicing, and with the risk of breast cancer, but not ovarian cancer, in BRCA1 pathogenic variant carriers. The identification of this genetic effect was confirmed by analogous observations in mouse cells and tissue in which a loxP sequence was inserted in the syntenic intronic region. The prediction that the rs5820483 minor allele variant would create a binding site for the splicing silencer hnRNP A1 was confirmed by pull-down assays. Our data suggest that perturbation of BRCA1 exon 11 splicing modifies the breast cancer risk conferred by pathogenic variants of this gene.
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Affiliation(s)
- Gorka Ruiz de Garibay
- ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
| | - Ignacio Fernandez-Garcia
- Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA
| | - Sylvie Mazoyer
- Equipe GENDEV, INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Université Lyon 1, Université St Etienne, Lyon, France
| | - Flavia Leme de Calais
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Pietro Ameri
- Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA
| | - Sangeetha Vijayakumar
- Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA
| | - Haydeliz Martinez-Ruiz
- Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA
| | - Francesca Damiola
- Department of Biopathology, Pathology Research Platform, Centre Léon Bérard, Lyon, France
| | - Laure Barjhoux
- Department of Biopathology, Pathology Research Platform, Centre Léon Bérard, Lyon, France
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
| | - Lars V B Andersen
- Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
| | - Carmen Herranz
- ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
| | - Francesca Mateo
- ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
| | - Luis Palomero
- ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
| | - Roderic Espín
- ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
| | - Antonio Gómez
- Gene Regulation, Stem Cells and Cancer, Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain
| | - Nadia García
- ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
| | - Daniel Jimenez
- ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
| | - Núria Bonifaci
- ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
| | - Ana I Extremera
- ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
| | - Julio Castaño
- Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL) and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), L'Hospitalet del Llobregat, Barcelona, Spain
| | - Angel Raya
- Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL) and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), L'Hospitalet del Llobregat, Barcelona, Spain.,Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.,Catalan Institution for Research and Advanced Studies, Barcelona, Spain
| | - Eduardo Eyras
- Catalan Institution for Research and Advanced Studies, Barcelona, Spain.,Department of Genome Sciences, The John Curtin School of Medical Research, EMBL Australia Partner Laboratory Network, Australian National University, Canberra, Australia
| | - Xose S Puente
- Department of Biochemistry and Molecular Biology, University Institute of Oncology, University of Oviedo, Oviedo, Spain.,Biomedical Research Centre in Cancer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
| | - Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, and Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain
| | - Conxi Lázaro
- Biomedical Research Centre in Cancer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain.,Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, and Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain
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- Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France
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- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
| | - Paolo Radice
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Research Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Daniel R Barnes
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
| | - Antonis C Antoniou
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
| | - Amanda B Spurdle
- Genetics and Computational Division, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Miguel de la Hoya
- Biomedical Research Centre in Cancer (CIBERONC), Instituto Salud Carlos III, Madrid, Spain.,Molecular Oncology Laboratory, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Diana Baralle
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.,Wessex Clinical Genetics Service, Southampton University Hospital NHS Trust, Southampton, UK
| | - Mary Helen Barcellos-Hoff
- Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA.,Department of Radiation Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USA
| | - Miquel A Pujana
- ProCURE, Oncobell, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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16
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Wendt C, Muranen TA, Mielikäinen L, Thutkawkorapin J, Blomqvist C, Jiao X, Ehrencrona H, Tham E, Arver B, Melin B, Kuchinskaya E, Stenmark Askmalm M, Paulsson-Karlsson Y, Einbeigi Z, von Wachenfeldt Väppling A, Kalso E, Tasmuth T, Kallioniemi A, Aittomäki K, Nevanlinna H, Borg Å, Lindblom A. A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients. Sci Rep 2021; 11:14763. [PMID: 34285278 PMCID: PMC8292481 DOI: 10.1038/s41598-021-93926-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 06/28/2021] [Indexed: 12/26/2022] Open
Abstract
The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.
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Affiliation(s)
- Camilla Wendt
- Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden.
| | - Taru A Muranen
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Lotta Mielikäinen
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Jessada Thutkawkorapin
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Stockholm, Sweden
| | - Carl Blomqvist
- Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Xiang Jiao
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Stockholm, Sweden
| | - Hans Ehrencrona
- Department of Clinical Genetics and Pathology, Office for Medical Services, Region Skåne, Lund, Sweden
| | - Emma Tham
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Stockholm, Sweden
| | - Brita Arver
- Department of Oncology-Pathology, Karolinska Institutet, Solna, Stockholm, Sweden
| | - Beatrice Melin
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Ekaterina Kuchinskaya
- Department of Clinical Genetics, Department of Clinical Experimental Medicine, Linköping University, Linköping, Sweden
| | - Marie Stenmark Askmalm
- Department of Clinical Genetics, Department of Clinical Experimental Medicine, Linköping University, Linköping, Sweden
| | | | - Zakaria Einbeigi
- Department of Oncology, Sahlgrenska University Hospital, 41345, Göteborg, Sweden
| | | | - Eija Kalso
- Department of Anaesthesiology, Intensive Care, and Pain Medicine, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Tiina Tasmuth
- Department of Anaesthesiology, Intensive Care, and Pain Medicine, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Anne Kallioniemi
- TAYS Cancer Centre and Faculty of Medicine and Health Technology, Tampere University; Fimlab Laboratories, Tampere University Hospital, Tampere, Finland
| | - Kristiina Aittomäki
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Heli Nevanlinna
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Åke Borg
- Department of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Stockholm, Sweden
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17
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Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6. Cancers (Basel) 2021; 13:cancers13112600. [PMID: 34073258 PMCID: PMC8197903 DOI: 10.3390/cancers13112600] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/21/2021] [Accepted: 05/22/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The most successful strategies for solid cancer immunotherapy have centered on targeting the co-stimulatory and co-inhibitory T cell molecules that regulate T cell activation. Although immunotherapy that targets surface receptors such as CTLA-4 and/or PD-1 with recombinant antibodies has been a game changer for cancer treatment, a sizeable subset of patients still fail to respond to, and even fewer patients are cured by, these therapy regimens. Here, we discuss the unique potential of NR2F6 as an emerging target for cancer immunotherapy to significantly increase response rates of cancer patients and/or to extend treatment to a broader range of cancer types. Abstract Additional therapeutic targets suitable for boosting anti-tumor effector responses have been found inside effector CD4+ and CD8+ T cells. It is likely that future treatment options will combine surface receptor and intracellular protein targets. Utilizing germline gene ablation as well as CRISPR/Cas9-mediated acute gene mutagenesis, the nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) has been firmly characterized as such an intracellular immune checkpoint in effector T cells. Targeting this receptor appears to be a strategy for improving anti-tumor immunotherapy responses, especially in combination with CTLA-4 and PD-1. Current preclinical experimental knowledge firmly validates the immune checkpoint function of NR2F6 in murine tumor models, which provides a promising perspective for immunotherapy regimens in humans in the near future. While the clinical focus remains on the B7/CD28 family members, protein candidate targets such as NR2F6 are now being investigated in laboratories around the world and in R&D companies. Such an alternative therapeutic approach, if demonstrated to be successful, could supplement the existing therapeutic models and significantly increase response rates of cancer patients and/or expand the reach of immune therapy regimens to include a wider range of cancer entities. In this perspective review, the role of NR2F6 as an emerging and druggable target in immuno-oncology research will be discussed, with special emphasis on the unique potential of NR2F6 and its critical and non-redundant role in both immune and tumor cells.
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18
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Stickeler E, Aktas B, Behrens A, Belleville E, Ditsch N, Fasching PA, Fehm TN, Hartkopf AD, Jackisch C, Janni W, Kolberg-Liedtke C, Kolberg HC, Lüftner D, Lux MP, Müller V, Schneeweiss A, Schütz F, Schulmeyer CE, Tesch H, Thomssen C, Uleer C, Untch M, Welslau M, Wöckel A, Wurmthaler LA, Würstlein R, Thill M. Update Breast Cancer 2021 Part 1 - Prevention and Early Stages. Geburtshilfe Frauenheilkd 2021; 81:526-538. [PMID: 34035547 PMCID: PMC8137274 DOI: 10.1055/a-1464-0953] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 03/23/2021] [Indexed: 12/17/2022] Open
Abstract
This review summarises not only the latest evidence on prevention, but also the current research on the treatment of early-stage breast cancer patients. Recent years have seen a growing body of evidence on the risk of high- and moderate-penetrance breast cancer susceptibility genes. A large international consortium has now been able to further refine the answer to the question of the significance of the so-called panel genes. Moreover, the data on treatment selection regarding endocrine efficacy and the decision for or against chemotherapy have also been advanced markedly. There is also new data on adjuvant CDK4/6 (cyclin-dependent kinase 4/6) inhibitors, which are standard in first-line treatment in patients with metastatic HER2-negative, hormone receptor-positive (HR+) breast cancer. For other therapies such as immune checkpoint inhibitors, which have successfully improved the rate of pathologic complete response (pCR) in neoadjuvant treatment settings for patients with triple-negative breast cancer (TNBC), there is a growing understanding of the quality of life and side effects. This is especially important in situations where patients could possibly be cured without such a regimen.
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Affiliation(s)
- Elmar Stickeler
- Department of Gynecology and Obstetrics, RWTH University Hospital Aachen, Aachen, Germany
| | - Bahriye Aktas
- Klinik und Poliklinik für Gynäkologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Annika Behrens
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | | | - Nina Ditsch
- Department of Gynecology and Obstetrics, University Hospital Augsburg, Augsburg, Germany
| | - Peter A. Fasching
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Tanja N. Fehm
- Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Andreas D. Hartkopf
- Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
| | - Christian Jackisch
- Department of Obstetrics and Gynecology, Sana Klinikum Offenbach, Offenbach, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | | | | | - Diana Lüftner
- Charité University Hospital, Department of Hematology, Oncology and Tumour Immunology, University Medicine Berlin, Berlin, Germany
| | - Michael P. Lux
- Klinik für Gynäkologie und Geburtshilfe, Frauenklinik St. Louise, Paderborn, St. Josefs-Krankenhaus, Salzkotten, Germany
| | - Volkmar Müller
- Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany
| | - Andreas Schneeweiss
- National Center for Tumor Diseases (NCT), Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Florian Schütz
- Gynäkologie und Geburtshilfe, Diakonissen-Stiftungs-Krankenhaus Speyer, Speyer, Germany
| | - Carla E. Schulmeyer
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Hans Tesch
- Oncology Practice at Bethanien Hospital Frankfurt, Frankfurt, Germany
| | - Christoph Thomssen
- Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Christoph Uleer
- Praxisgemeinschaft Frauenärzte am Bahnhofsplatz, Hildesheim, Germany
| | - Michael Untch
- Clinic for Gynecology and Obstetrics, Breast Cancer Center, Genecologic Oncology Center, Helios Klinikum Berlin Buch, Berlin, Germany
| | | | - Achim Wöckel
- Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
| | - Lena A. Wurmthaler
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Rachel Würstlein
- Breast Center, Department of Gynecology and Obstetrics and CCC Munich LMU, LMU University Hospital, Munich, Germany
| | - Marc Thill
- Agaplesion Markus Krankenhaus, Department of Gynecology and Gynecological Oncology, Frankfurt, Germany
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19
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Martini R, Chen Y, Jenkins BD, Elhussin IA, Cheng E, Hoda SA, Ginter PS, Hanover J, Zeidan RB, Oppong JK, Adjei EK, Jibril A, Chitale D, Bensenhaver JM, Awuah B, Bekele M, Abebe E, Kyei I, Aitpillah FS, Adinku MO, Ankomah K, Osei-Bonsu EB, Nathansan SD, Jackson L, Jiagge E, Petersen LF, Proctor E, Nikolinakos P, Gyan KK, Yates C, Kittles R, Newman LA, Davis MB. Investigation of triple-negative breast cancer risk alleles in an International African-enriched cohort. Sci Rep 2021; 11:9247. [PMID: 33927264 PMCID: PMC8085076 DOI: 10.1038/s41598-021-88613-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/12/2021] [Indexed: 11/09/2022] Open
Abstract
Large-scale efforts to identify breast cancer (BC) risk alleles have historically taken place among women of European ancestry. Recently, there are new efforts to verify if these alleles increase risk in African American (AA) women as well. We investigated the effect of previously reported AA breast cancer and triple-negative breast cancer (TNBC) risk alleles in our African-enriched International Center for the Study of Breast Cancer Subtypes (ICSBCS) cohort. Using case-control, case-series and race-nested approaches, we report that the Duffy-null allele (rs2814778) is associated with TNBC risk (OR = 3.814, p = 0.001), specifically among AA individuals, after adjusting for self-indicated race and west African ancestry (OR = 3.368, p = 0.007). We have also validated the protective effect of the minor allele of the ANKLE1 missense variant rs2363956 among AA for TNBC (OR = 0.420, p = 0.005). Our results suggest that an ancestry-specific Duffy-null allele and differential prevalence of a polymorphic gene variant of ANKLE1 may play a role in TNBC breast cancer outcomes. These findings present opportunities for therapeutic potential and future studies to address race-specific differences in TNBC risk and disease outcome.
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Affiliation(s)
- Rachel Martini
- Department of Surgery, Weill Cornell Medicine, 420 E 70th Street, New York City, NY, 10021, USA
- Department of Genetics, University of Georgia, Athens, GA, USA
| | - Yalei Chen
- Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA
- Center for Bioinformatics, Henry Ford Health System, Detroit, MI, USA
| | - Brittany D Jenkins
- Department of Surgery, Weill Cornell Medicine, 420 E 70th Street, New York City, NY, 10021, USA
- Department of Genetics, University of Georgia, Athens, GA, USA
| | - Isra A Elhussin
- Department of Biology & Center for Cancer Research, Tuskegee University, Tuskegee, AL, USA
| | - Esther Cheng
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Syed A Hoda
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Paula S Ginter
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | | | - Rozina B Zeidan
- Department of Surgery, Weill Cornell Medicine, 420 E 70th Street, New York City, NY, 10021, USA
| | - Joseph K Oppong
- Department of Surgery, Komfo Anokye Teaching Hospital, Kumasi, Ghana
| | - Ernest K Adjei
- Department of Pathology, Komfo Anokye Teaching Hospital, Kumasi, Ghana
| | - Aisha Jibril
- Department of Pathology, St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | | | | | - Baffour Awuah
- Directorate of Oncology, Komfo Anokye Teaching Hospital, Kumasi, Ghana
| | - Mahteme Bekele
- Department of Surgery, St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | - Engida Abebe
- Department of Surgery, St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | - Ishmael Kyei
- Department of Surgery, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Frances S Aitpillah
- Department of Surgery, Komfo Anokye Teaching Hospital, Kumasi, Ghana
- Department of Surgery, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Michael O Adinku
- Department of Surgery, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Kwasi Ankomah
- Directorate of Radiology, Komfo Anokye Teaching Hospital, Kumasi, Ghana
| | | | | | - LaToya Jackson
- Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA
| | - Evelyn Jiagge
- Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA
| | | | - Erica Proctor
- Department of Surgery, Henry Ford Health System, Detroit, MI, USA
| | | | - Kofi K Gyan
- Department of Surgery, Weill Cornell Medicine, 420 E 70th Street, New York City, NY, 10021, USA
| | - Clayton Yates
- Department of Biology & Center for Cancer Research, Tuskegee University, Tuskegee, AL, USA
| | - Rick Kittles
- Department of Population Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Lisa A Newman
- Department of Surgery, Weill Cornell Medicine, 420 E 70th Street, New York City, NY, 10021, USA
| | - Melissa B Davis
- Department of Surgery, Weill Cornell Medicine, 420 E 70th Street, New York City, NY, 10021, USA.
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20
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Tang X, Zhang T, Cheng N, Wang H, Zheng CH, Xia J, Zhang T. usDSM: a novel method for deleterious synonymous mutation prediction using undersampling scheme. Brief Bioinform 2021; 22:6236069. [PMID: 33866367 DOI: 10.1093/bib/bbab123] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 12/11/2022] Open
Abstract
Although synonymous mutations do not alter the encoded amino acids, they may impact protein function by interfering with the regulation of RNA splicing or altering transcript splicing. New progress on next-generation sequencing technologies has put the exploration of synonymous mutations at the forefront of precision medicine. Several approaches have been proposed for predicting the deleterious synonymous mutations specifically, but their performance is limited by imbalance of the positive and negative samples. In this study, we firstly expanded the number of samples greatly from various data sources and compared six undersampling strategies to solve the problem of the imbalanced datasets. The results suggested that cluster centroid is the most effective scheme. Secondly, we presented a computational model, undersampling scheme based method for deleterious synonymous mutation (usDSM) prediction, using 14-dimensional biology features and random forest classifier to detect the deleterious synonymous mutation. The results on the test datasets indicated that the proposed usDSM model can attain superior performance in comparison with other state-of-the-art machine learning methods. Lastly, we found that the deep learning model did not play a substantial role in deleterious synonymous mutation prediction through a lot of experiments, although it achieves superior results in other fields. In conclusion, we hope our work will contribute to the future development of computational methods for a more accurate prediction of the deleterious effect of human synonymous mutation. The web server of usDSM is freely accessible at http://usdsm.xialab.info/.
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Affiliation(s)
- Xi Tang
- GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University and the Institutes of Physical Science and Information Technology, Anhui University, China
| | - Tao Zhang
- School of Computer Science and Technology, Anhui University, China
| | - Na Cheng
- Institutes of Physical Science and Information Technology, Anhui University, China
| | - Huadong Wang
- School of Computer Science and Technology, Anhui University, China
| | - Chun-Hou Zheng
- School of Computer Science and Technology, Anhui University, China
| | - Junfeng Xia
- Institutes of Physical Science and Information Technology, Anhui University, China
| | - Tiejun Zhang
- GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, China
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21
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Woodward ER, van Veen EM, Evans DG. From BRCA1 to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes. Breast Care (Basel) 2021; 16:202-213. [PMID: 34248461 DOI: 10.1159/000515319] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 02/16/2021] [Indexed: 12/12/2022] Open
Abstract
Background There has been huge progress over the last 30 years in identifying the familial component of breast cancer. Summary Currently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes ATM and CHEK2. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40-90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. Key-Messages There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as CDH1 and TP53, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.
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Affiliation(s)
- Emma R Woodward
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.,Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Elke M van Veen
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.,Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - D Gareth Evans
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.,Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.,PREVENT Breast Cancer Prevention Centre, Nightingale Centre, Manchester Universities Foundation Trust, Wythenshawe Hospital, Manchester, United Kingdom.,Manchester Breast Centre, Manchester Cancer Research Centre, The Christie, University of Manchester, Manchester, United Kingdom
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22
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Coignard J, Lush M, Beesley J, O'Mara TA, Dennis J, Tyrer JP, Barnes DR, McGuffog L, Leslie G, Bolla MK, Adank MA, Agata S, Ahearn T, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Arnold N, Aronson KJ, Arun BK, Augustinsson A, Azzollini J, Barrowdale D, Baynes C, Becher H, Bermisheva M, Bernstein L, Białkowska K, Blomqvist C, Bojesen SE, Bonanni B, Borg A, Brauch H, Brenner H, Burwinkel B, Buys SS, Caldés T, Caligo MA, Campa D, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Chung WK, Claes KBM, Clarke CL, Collée JM, Conroy DM, Czene K, Daly MB, Devilee P, Diez O, Ding YC, Domchek SM, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Eliassen AH, Engel C, Eriksson M, Evans DG, Fasching PA, Flyger H, Fostira F, Friedman E, Fritschi L, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, Garcia-Barberan V, García-Closas M, García-Sáenz JA, Gaudet MM, Gayther SA, Gehrig A, Georgoulias V, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hart SN, He W, Hogervorst FBL, Hollestelle A, Hopper JL, Horcasitas DJ, Hulick PJ, et alCoignard J, Lush M, Beesley J, O'Mara TA, Dennis J, Tyrer JP, Barnes DR, McGuffog L, Leslie G, Bolla MK, Adank MA, Agata S, Ahearn T, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Arnold N, Aronson KJ, Arun BK, Augustinsson A, Azzollini J, Barrowdale D, Baynes C, Becher H, Bermisheva M, Bernstein L, Białkowska K, Blomqvist C, Bojesen SE, Bonanni B, Borg A, Brauch H, Brenner H, Burwinkel B, Buys SS, Caldés T, Caligo MA, Campa D, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Chung WK, Claes KBM, Clarke CL, Collée JM, Conroy DM, Czene K, Daly MB, Devilee P, Diez O, Ding YC, Domchek SM, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Eliassen AH, Engel C, Eriksson M, Evans DG, Fasching PA, Flyger H, Fostira F, Friedman E, Fritschi L, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, Garcia-Barberan V, García-Closas M, García-Sáenz JA, Gaudet MM, Gayther SA, Gehrig A, Georgoulias V, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hart SN, He W, Hogervorst FBL, Hollestelle A, Hopper JL, Horcasitas DJ, Hulick PJ, Hunter DJ, Imyanitov EN, Jager A, Jakubowska A, James PA, Jensen UB, John EM, Jones ME, Kaaks R, Kapoor PM, Karlan BY, Keeman R, Khusnutdinova E, Kiiski JI, Ko YD, Kosma VM, Kraft P, Kurian AW, Laitman Y, Lambrechts D, Le Marchand L, Lester J, Lesueur F, Lindstrom T, Lopez-Fernández A, Loud JT, Luccarini C, Mannermaa A, Manoukian S, Margolin S, Martens JWM, Mebirouk N, Meindl A, Miller A, Milne RL, Montagna M, Nathanson KL, Neuhausen SL, Nevanlinna H, Nielsen FC, O'Brien KM, Olopade OI, Olson JE, Olsson H, Osorio A, Ottini L, Park-Simon TW, Parsons MT, Pedersen IS, Peshkin B, Peterlongo P, Peto J, Pharoah PDP, Phillips KA, Polley EC, Poppe B, Presneau N, Pujana MA, Punie K, Radice P, Rantala J, Rashid MU, Rennert G, Rennert HS, Robson M, Romero A, Rossing M, Saloustros E, Sandler DP, Santella R, Scheuner MT, Schmidt MK, Schmidt G, Scott C, Sharma P, Soucy P, Southey MC, Spinelli JJ, Steinsnyder Z, Stone J, Stoppa-Lyonnet D, Swerdlow A, Tamimi RM, Tapper WJ, Taylor JA, Terry MB, Teulé A, Thull DL, Tischkowitz M, Toland AE, Torres D, Trainer AH, Truong T, Tung N, Vachon CM, Vega A, Vijai J, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wolk A, Yadav S, Yang XR, Yannoukakos D, Zheng W, Ziogas A, Zorn KK, Park SK, Thomassen M, Offit K, Schmutzler RK, Couch FJ, Simard J, Chenevix-Trench G, Easton DF, Andrieu N, Antoniou AC. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers. Nat Commun 2021; 12:1078. [PMID: 33990587 PMCID: PMC7890067 DOI: 10.1038/s41467-020-20496-3] [Show More Authors] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 11/19/2020] [Indexed: 02/02/2023] Open
Abstract
Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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Affiliation(s)
- Juliette Coignard
- Genetic Epidemiology of Cancer team, Inserm, U900, Paris, France
- Institut Curie Paris, Paris, France
- Mines ParisTech Fontainebleau, Paris, France
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- PSL University Paris, Paris, France
- Paris Sud University, Orsay, France
| | - Michael Lush
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Jonathan Beesley
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Tracy A O'Mara
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Joe Dennis
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Jonathan P Tyrer
- Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK
| | - Daniel R Barnes
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Lesley McGuffog
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Goska Leslie
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Manjeet K Bolla
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Muriel A Adank
- Family Cancer Clinic, The Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
| | - Simona Agata
- Immunology and Molecular Oncology, Unit Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Thomas Ahearn
- Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Kristiina Aittomäki
- Department of Clinical Genetics, Helsinki University Hospital University of Helsinki, Helsinki, Finland
| | - Irene L Andrulis
- Fred A. Litwin Center for Cancer Genetics Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics University of Toronto, Toronto, ON, Canada
| | - Hoda Anton-Culver
- Department of Epidemiology, Genetic Epidemiology Research Institute University of California Irvine, Irvine, CA, USA
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Norbert Arnold
- Department of Gynaecology and Obstetrics University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany
- Institute of Clinical Molecular Biology University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany
| | - Kristan J Aronson
- Department of Public Health Sciences, and Cancer Research Institute Queen's University, Kingston, ON, Canada
| | - Banu K Arun
- Department of Breast Medical Oncology University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Annelie Augustinsson
- Department of Cancer Epidemiology, Clinical Sciences Lund University, Lund, 22242, Sweden
| | - Jacopo Azzollini
- Unit of Medical Genetics, Department of Medical Oncology and Hematology Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Daniel Barrowdale
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Caroline Baynes
- Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK
| | - Heiko Becher
- Institute for Medical Biometrics and Epidemiology University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marina Bermisheva
- Institute of Biochemistry and Genetics Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia
| | - Leslie Bernstein
- Department of Population Sciences Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Katarzyna Białkowska
- Department of Genetics and Pathology Pomeranian Medical University Szczecin, Szczecin, Poland
| | - Carl Blomqvist
- Department of Oncology, Helsinki University Hospital University of Helsinki, Helsinki, Finland
- Department of Oncology Örebro University Hospital, Örebro, Sweden
| | - Stig E Bojesen
- Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark
- Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark
| | - Bernardo Bonanni
- Division of Cancer Prevention and Genetics IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Ake Borg
- Department of Oncology Lund University and Skåne University Hospital, Lund, Sweden
| | - Hiltrud Brauch
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
- iFIT-Cluster of Excellence University of Tübingen, Tübingen, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Barbara Burwinkel
- Molecular Epidemiology Group, C080 German Cancer Research Center (DKFZ), Heidelberg, Germany
- Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg University of Heidelberg, Heidelberg, Germany
| | - Saundra S Buys
- Department of Medicine Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Trinidad Caldés
- Molecular Oncology Laboratory CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain
| | - Maria A Caligo
- SOD Genetica Molecolare University Hospital, Pisa, Italy
| | - Daniele Campa
- Department of Biology University of Pisa, Pisa, Italy
- Division of Cancer Epidemiology German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Brian D Carter
- Behavioral and Epidemiology Research Group American Cancer Society Atlanta, Atlanta, GA, USA
| | - Jose E Castelao
- Oncology and Genetics Unit Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology German Cancer Research Center (DKFZ), Heidelberg, Germany
- Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH) University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Wendy K Chung
- Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA
| | | | - Christine L Clarke
- Westmead Institute for Medical Research University of Sydney, Sydney, NSW, Australia
| | - J Margriet Collée
- Department of Clinical Genetics Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Don M Conroy
- Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK
| | - Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Mary B Daly
- Department of Clinical Genetics Fox Chase Cancer Center Philadelphia, Philadelphia, PA, USA
| | - Peter Devilee
- Department of Pathology Leiden University Medical Center, Leiden, The Netherlands
- Department of Human Genetics Leiden University Medical Center, Leiden, The Netherlands
| | - Orland Diez
- Oncogenetics Group Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Clinical and Molecular Genetics Area University Hospital Vall d'Hebron, Barcelona, Spain
| | - Yuan Chun Ding
- Department of Population Sciences Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Susan M Domchek
- Basser Center for BRCA, Abramson Cancer Center University of Pennsylvania, Philadelphia, PA, USA
| | - Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Isabel Dos-Santos-Silva
- Department of Non-Communicable Disease Epidemiology London School of Hygiene and Tropical Medicine, London, UK
| | - Alison M Dunning
- Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK
| | - Miriam Dwek
- School of Life Sciences University of Westminster, London, UK
| | - Diana M Eccles
- Faculty of Medicine University of Southampton, Southampton, UK
| | - A Heather Eliassen
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Epidemiology Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Christoph Engel
- Institute for Medical Informatics, Statistics and Epidemiology University of Leipzig, Leipzig, Germany
| | - Mikael Eriksson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - D Gareth Evans
- Genomic Medicine, Division of Evolution and Genomic Sciences The University of Manchester, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St Mary's Hospital, Manchester, UK
- Genomic Medicine, North West Genomics hub Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St Mary's Hospital, Manchester, UK
| | - Peter A Fasching
- David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology University of California at Los Angeles, Los Angeles, CA, USA
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Erlangen, Germany
| | - Henrik Flyger
- Department of Breast Surgery, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark
| | - Florentia Fostira
- Molecular Diagnostics Laboratory, INRASTES National Centre for Scientific Research íDemokritosí, Athens, Greece
| | - Eitan Friedman
- The Susanne Levy Gertner Oncogenetics Unit Chaim Sheba Medical Center, Ramat Gan, Israel
- Sackler Faculty of Medicine Tel Aviv University, Ramat Aviv, Israel
| | - Lin Fritschi
- School of Public Health Curtin University, Perth, Western Australia, Australia
| | - Debra Frost
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Manuela Gago-Dominguez
- Genomic Medicine Group, Galician Foundation of Genomic Medicine Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
- Moores Cancer Center University of California, San Diego La Jolla, CA, USA
| | - Susan M Gapstur
- Behavioral and Epidemiology Research Group American Cancer Society Atlanta, Atlanta, GA, USA
| | - Judy Garber
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Vanesa Garcia-Barberan
- Medical Oncology Department, Hospital Clínico San Carlos Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Montserrat García-Closas
- Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - José A García-Sáenz
- Medical Oncology Department, Hospital Clínico San Carlos Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Mia M Gaudet
- Behavioral and Epidemiology Research Group American Cancer Society Atlanta, Atlanta, GA, USA
| | - Simon A Gayther
- Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Andrea Gehrig
- Department of Human Genetics University Würzburg, Würzburg, Germany
| | | | - Graham G Giles
- Cancer Epidemiology Division Cancer Council Victoria, Melbourne, VIC, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health Monash University, Clayton, VIC, Australia
| | - Andrew K Godwin
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Mark S Goldberg
- Department of Medicine, McGill University, Montréal, QC, Canada
- Division of Clinical Epidemiology, Royal Victoria Hospital McGill University Montréal, Montréal, QC, Canada
| | - David E Goldgar
- Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Anna González-Neira
- Human Cancer Genetics Programme Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Mark H Greene
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics National Cancer Institute, Bethesda, MD, USA
| | - Pascal Guénel
- Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP) INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
| | - Lothar Haeberle
- Department of Gynaecology and Obstetrics, University Hospital Erlangen Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
| | - Eric Hahnen
- Center for Hereditary Breast and Ovarian Cancer Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology (CIO) Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Christopher A Haiman
- Department of Preventive Medicine, Keck School of Medicine University of Southern California, Los Angeles, CA, USA
| | | | - Per Hall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Oncology, Södersjukhuset, Stockholm, Sweden
| | - Ute Hamann
- Molecular Genetics of Breast Cancer German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Patricia A Harrington
- Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK
| | - Steven N Hart
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Wei He
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Frans B L Hogervorst
- Family Cancer Clinic, The Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
| | - Antoinette Hollestelle
- Department of Medical Oncology, Family Cancer Clinic Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - John L Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Darling J Horcasitas
- New Mexico Oncology Hematology Consultants, University of New Mexico, Albuquerque, NM, USA
| | - Peter J Hulick
- Center for Medical Genetics NorthShore University HealthSystem, Evanston, IL, USA
- The University of Chicago Pritzker School of Medicine Chicago, Chicago, IL, USA
| | - David J Hunter
- Department of Epidemiology Harvard TH Chan School of Public Health, Boston, MA, USA
- Program in Genetic Epidemiology and Statistical Genetics Harvard TH Chan School of Public Health Boston, Boston, MA, USA
- Nuffield Department of Population Health University of Oxford, Oxford, UK
| | | | - Agnes Jager
- Department of Medical Oncology, Family Cancer Clinic Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Anna Jakubowska
- Department of Genetics and Pathology Pomeranian Medical University Szczecin, Szczecin, Poland
- Independent Laboratory of Molecular Biology and Genetic Diagnostics Pomeranian Medical University, Szczecin, Poland
| | - Paul A James
- Sir Peter MacCallum Department of Oncology The University of Melbourne, Melbourne, VIC, Australia
- Parkville Familial Cancer Centre Peter MacCallum Cancer Center, Melbourne, VIC, Australia
| | - Uffe Birk Jensen
- Department of Clinical Genetics Aarhus, University Hospital, Aarhus, Denmark
| | - Esther M John
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA
| | - Michael E Jones
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA
| | - Rudolf Kaaks
- Division of Cancer Epidemiology German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Pooja Middha Kapoor
- Division of Cancer Epidemiology German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Genetics and Epidemiology The Institute of Cancer Research, London, UK
| | - Beth Y Karlan
- Faculty of Medicine University of Heidelberg, Heidelberg, Germany
- David Geffen School of Medicine, Department of Obstetrics and Gynecology University of California at Los Angeles, Los Angeles, CA, USA
| | - Renske Keeman
- Womenís Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Elza Khusnutdinova
- Institute of Biochemistry and Genetics Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia
- Division of Molecular Pathology The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Johanna I Kiiski
- Department of Genetics and Fundamental Medicine Bashkir State Medical University, Ufa, Russia
| | - Yon-Dschun Ko
- Department of Obstetrics and Gynecology, Helsinki University Hospital University of Helsinki, Helsinki, Finland
| | - Veli-Matti Kosma
- Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH Johanniter Krankenhaus, Bonn, Germany
- Translational Cancer Research Area University of Eastern Finland, Kuopio, Finland
- Institute of Clinical Medicine, Pathology and Forensic Medicine University of Eastern Finland, Kuopio, Finland
| | - Peter Kraft
- Department of Epidemiology Harvard TH Chan School of Public Health, Boston, MA, USA
- Program in Genetic Epidemiology and Statistical Genetics Harvard TH Chan School of Public Health Boston, Boston, MA, USA
| | - Allison W Kurian
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA
| | - Yael Laitman
- The Susanne Levy Gertner Oncogenetics Unit Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Diether Lambrechts
- VIB Center for Cancer Biology, Leuven, Belgium
- Laboratory for Translational Genetics, Department of Human Genetics University of Leuven, Leuven, Belgium
| | - Loic Le Marchand
- Epidemiology Program University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Jenny Lester
- Faculty of Medicine University of Heidelberg, Heidelberg, Germany
- David Geffen School of Medicine, Department of Obstetrics and Gynecology University of California at Los Angeles, Los Angeles, CA, USA
| | - Fabienne Lesueur
- Genetic Epidemiology of Cancer team, Inserm, U900, Paris, France
- Institut Curie Paris, Paris, France
- Mines ParisTech Fontainebleau, Paris, France
- PSL University Paris, Paris, France
| | - Tricia Lindstrom
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Adria Lopez-Fernández
- High Risk and Cancer Prevention Group Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Jennifer T Loud
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics National Cancer Institute, Bethesda, MD, USA
| | - Craig Luccarini
- Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK
| | - Arto Mannermaa
- Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH Johanniter Krankenhaus, Bonn, Germany
- Translational Cancer Research Area University of Eastern Finland, Kuopio, Finland
- Institute of Clinical Medicine, Pathology and Forensic Medicine University of Eastern Finland, Kuopio, Finland
| | - Siranoush Manoukian
- Unit of Medical Genetics, Department of Medical Oncology and Hematology Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Sara Margolin
- Department of Oncology, Södersjukhuset, Stockholm, Sweden
- Department of Clinical Science and Education, Södersjukhuset Karolinska Institutet, Stockholm, Sweden
| | - John W M Martens
- Department of Medical Oncology, Family Cancer Clinic Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Noura Mebirouk
- Genetic Epidemiology of Cancer team, Inserm, U900, Paris, France
- Institut Curie Paris, Paris, France
- Mines ParisTech Fontainebleau, Paris, France
- PSL University Paris, Paris, France
| | - Alfons Meindl
- Department of Gynecology and Obstetrics University of Munich, Campus Grosshadern, Munich, Germany
| | - Austin Miller
- NRG Oncology, Statistics and Data Management Center Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Roger L Milne
- Cancer Epidemiology Division Cancer Council Victoria, Melbourne, VIC, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health Monash University, Clayton, VIC, Australia
| | - Marco Montagna
- Immunology and Molecular Oncology, Unit Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - Katherine L Nathanson
- Basser Center for BRCA, Abramson Cancer Center University of Pennsylvania, Philadelphia, PA, USA
| | - Susan L Neuhausen
- Department of Population Sciences Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Heli Nevanlinna
- Department of Genetics and Fundamental Medicine Bashkir State Medical University, Ufa, Russia
| | - Finn C Nielsen
- Center for Genomic Medicine Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Katie M O'Brien
- Epidemiology Branch National Institute of Environmental Health Sciences, NIH Research Triangle Park, Durham, NC, USA
| | | | - Janet E Olson
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Håkan Olsson
- Department of Cancer Epidemiology, Clinical Sciences Lund University, Lund, 22242, Sweden
| | - Ana Osorio
- Human Cancer Genetics Programme Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | - Laura Ottini
- Department of Molecular Medicine University La Sapienza, Rome, Italy
| | | | - Michael T Parsons
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Inge Sokilde Pedersen
- Molecular Diagnostics Aalborg University Hospital, Aalborg, Denmark
- Clinical Cancer Research Center Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine Aalborg University, Aalborg, Denmark
| | - Beth Peshkin
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Paolo Peterlongo
- Genome Diagnostics Program IFOM - the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
| | - Julian Peto
- Department of Non-Communicable Disease Epidemiology London School of Hygiene and Tropical Medicine, London, UK
| | - Paul D P Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK
| | - Kelly-Anne Phillips
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology The University of Melbourne, Melbourne, VIC, Australia
| | - Eric C Polley
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Bruce Poppe
- Centre for Medical Genetics Ghent University, Gent, Belgium
| | - Nadege Presneau
- School of Life Sciences University of Westminster, London, UK
| | - Miquel Angel Pujana
- Translational Research Laboratory IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, CIBERONC, Barcelona, Spain
| | - Kevin Punie
- Leuven Multidisciplinary Breast Center, Department of Oncology Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
| | - Paolo Radice
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
| | | | - Muhammad U Rashid
- Molecular Genetics of Breast Cancer German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Basic Sciences Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan
| | - Gad Rennert
- Clalit National Cancer Control Center Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
| | - Hedy S Rennert
- Clalit National Cancer Control Center Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
| | - Mark Robson
- Clinical Genetics Service, Department of Medicine Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Atocha Romero
- Medical Oncology Department Hospital Universitario Puerta de Hierro, Madrid, Spain
| | - Maria Rossing
- Center for Genomic Medicine Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Dale P Sandler
- Epidemiology Branch National Institute of Environmental Health Sciences, NIH Research Triangle Park, Durham, NC, USA
| | - Regina Santella
- Department of Epidemiology, Mailman School of Public Health Columbia University, New York, NY, USA
| | - Maren T Scheuner
- Cancer Genetics and Prevention Program University of California San Francisco, San Francisco, CA, USA
| | - Marjanka K Schmidt
- Womenís Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Psychosocial Research and Epidemiology The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
| | - Gunnar Schmidt
- Institute of Human Genetics Hannover Medical School, Hannover, Germany
| | - Christopher Scott
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Priyanka Sharma
- Department of Internal Medicine, Division of Medical Oncology University of Kansas Medical Center, Westwood, KS, USA
| | - Penny Soucy
- Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada
| | - Melissa C Southey
- Precision Medicine, School of Clinical Sciences at Monash Health Monash University, Clayton, VIC, Australia
- Department of Clinical Pathology The University of Melbourne, Melbourne, VIC, Australia
| | - John J Spinelli
- Population Oncology BC Cancer, Vancouver, BC, Canada
- School of Population and Public Health University of British Columbia, Vancouver, BC, Canada
| | - Zoe Steinsnyder
- Clinical Genetics Research Lab, Department of Cancer Biology and Genetics Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Jennifer Stone
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
- The Curtin UWA Centre for Genetic Origins of Health and Disease Curtin University and University of Western Australia, Perth, Western Australia, Australia
| | - Dominique Stoppa-Lyonnet
- Service de Génétique Institut Curie, Paris, France
- Department of Tumour Biology INSERM U830, Paris, France
- Université Paris Descartes, Paris, France
| | - Anthony Swerdlow
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA
- Division of Breast Cancer Research Institute of Cancer Research, London, UK
| | - Rulla M Tamimi
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Epidemiology Harvard TH Chan School of Public Health, Boston, MA, USA
- Program in Genetic Epidemiology and Statistical Genetics Harvard TH Chan School of Public Health Boston, Boston, MA, USA
| | | | - Jack A Taylor
- Epidemiology Branch National Institute of Environmental Health Sciences, NIH Research Triangle Park, Durham, NC, USA
- Epigenetic and Stem Cell Biology Laboratory National Institute of Environmental Health Sciences, NIH Research Triangle Park, Triangle Park, NC, USA
| | - Mary Beth Terry
- Department of Epidemiology, Mailman School of Public Health Columbia University, New York, NY, USA
| | - Alex Teulé
- Hereditary Cancer Program ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain
| | - Darcy L Thull
- Department of Medicine Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Marc Tischkowitz
- Program in Cancer Genetics, Departments of Human Genetics and Oncology McGill University, Montréal, QC, Canada
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Center, University of Cambridge, Cambridge, UK
| | - Amanda E Toland
- Department of Cancer Biology and Genetics The Ohio State University, Columbus, OH, USA
| | - Diana Torres
- Molecular Genetics of Breast Cancer German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Human Genetics Pontificia Universidad Javeriana, Bogota, Colombia
| | - Alison H Trainer
- Parkville Familial Cancer Centre Peter MacCallum Cancer Center, Melbourne, VIC, Australia
- Department of medicine University Of Melbourne, Melbourne, VIC, Australia
| | - Thérèse Truong
- Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP) INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
| | - Nadine Tung
- Department of Medical Oncology Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Celine M Vachon
- Department of Health Science Research, Division of Epidemiology Mayo Clinic, Rochester, MN, USA
| | - Ana Vega
- Fundación Pública Galega Medicina Xenómica-SERGAS, Instituto de Investigación Sanitaria Santiago de Compostela (IDIS); CIBERER, Santiago de Compostela, Spain
| | - Joseph Vijai
- Clinical Genetics Service, Department of Medicine Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Clinical Genetics Research Lab, Department of Cancer Biology and Genetics Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Qin Wang
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Barbara Wappenschmidt
- Center for Hereditary Breast and Ovarian Cancer Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology (CIO) Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Clarice R Weinberg
- Biostatistics and Computational Biology Branch National Institute of Environmental Health Sciences, NIH Research Triangle Park, Triangle Park, NC, USA
| | | | - Camilla Wendt
- Department of Clinical Science and Education, Södersjukhuset Karolinska Institutet, Stockholm, Sweden
| | - Alicja Wolk
- Institute of Environmental Medicine Karolinska Institutet, Stockholm, Sweden
- Department of Surgical Sciences Uppsala University, Uppsala, Sweden
| | | | - Xiaohong R Yang
- Division of Cancer Epidemiology and Genetics National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Drakoulis Yannoukakos
- Molecular Diagnostics Laboratory, INRASTES National Centre for Scientific Research íDemokritosí, Athens, Greece
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Argyrios Ziogas
- Department of Epidemiology, Genetic Epidemiology Research Institute University of California Irvine, Irvine, CA, USA
| | - Kristin K Zorn
- Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sue K Park
- Department of Preventive Medicine Seoul National University College of Medicine, Seoul, Korea
- Department of Biomedical Sciences Seoul National University Graduate School, Seoul, Korea
- Cancer Research Institute Seoul National University, Seoul, Korea
| | - Mads Thomassen
- Department of Clinical Genetics Odense University Hospital, Odence C, Denmark
| | - Kenneth Offit
- Clinical Genetics Service, Department of Medicine Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Clinical Genetics Research Lab, Department of Cancer Biology and Genetics Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Rita K Schmutzler
- Center for Hereditary Breast and Ovarian Cancer Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology (CIO) Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Fergus J Couch
- Department of Laboratory Medicine and Pathology Mayo Clinic, Rochester, MN, USA
| | - Jacques Simard
- Department of Epidemiology, Genetic Epidemiology Research Institute University of California Irvine, Irvine, CA, USA
| | - Georgia Chenevix-Trench
- Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Douglas F Easton
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK
| | - Nadine Andrieu
- Genetic Epidemiology of Cancer team, Inserm, U900, Paris, France.
- Institut Curie Paris, Paris, France.
- Mines ParisTech Fontainebleau, Paris, France.
- PSL University Paris, Paris, France.
| | - Antonis C Antoniou
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
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23
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Moslehi R, Tsao HS, Zeinomar N, Stagnar C, Fitzpatrick S, Dzutsev A. Integrative genomic analysis implicates ERCC6 and its interaction with ERCC8 in susceptibility to breast cancer. Sci Rep 2020; 10:21276. [PMID: 33277540 PMCID: PMC7718875 DOI: 10.1038/s41598-020-77037-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
Up to 30% of all breast cancer cases may be inherited and up to 85% of those may be due to segregation of susceptibility genes with low and moderate risk [odds ratios (OR) ≤ 3] for (mostly peri- and post-menopausal) breast cancer. The majority of low/moderate-risk genes, particularly those with minor allele frequencies (MAF) of < 30%, have not been identified and/or validated due to limitations of conventional association testing approaches, which include the agnostic nature of Genome Wide Association Studies (GWAS). To overcome these limitations, we used a hypothesis-driven integrative genomics approach to test the association of breast cancer with candidate genes by analyzing multi-omics data. Our candidate-gene association analyses of GWAS datasets suggested an increased risk of breast cancer with ERCC6 (main effect: 1.29 ≤ OR ≤ 2.91, 0.005 ≤ p ≤ 0.04, 11.8 ≤ MAF ≤ 40.9%), and implicated its interaction with ERCC8 (joint effect: 3.03 ≤ OR ≤ 5.31, 0.01 ≤ pinteraction ≤ 0.03). We found significant upregulation of ERCC6 (p = 7.95 × 10-6) and ERCC8 (p = 4.67 × 10-6) in breast cancer and similar frequencies of ERCC6 (1.8%) and ERCC8 (0.3%) mutations in breast tumors to known breast cancer susceptibility genes such as BLM (1.9%) and LSP1 (0.3%). Our integrative genomics approach suggests that ERCC6 may be a previously unreported low- to moderate-risk breast cancer susceptibility gene, which may also interact with ERCC8.
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Affiliation(s)
- Roxana Moslehi
- School of Public Health, Cancer Research Center, University at Albany, State University of New York (SUNY), Albany, NY, 12144, USA.
| | - Hui-Shien Tsao
- School of Public Health, Cancer Research Center, University at Albany, State University of New York (SUNY), Albany, NY, 12144, USA
- New York State Office of Children and Family Services, New York, USA
| | - Nur Zeinomar
- School of Public Health, Cancer Research Center, University at Albany, State University of New York (SUNY), Albany, NY, 12144, USA
- Mailman School of Public Health, Columbia University, New York, USA
| | - Cristy Stagnar
- School of Public Health, Cancer Research Center, University at Albany, State University of New York (SUNY), Albany, NY, 12144, USA
- Drukier Institute for Children's Health, Weill Cornell Medicine, New York, USA
| | - Sean Fitzpatrick
- School of Public Health, Cancer Research Center, University at Albany, State University of New York (SUNY), Albany, NY, 12144, USA
| | - Amiran Dzutsev
- Cancer Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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24
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Huober J, Schneeweiss A, Hartkopf AD, Müller V, Lux MP, Janni W, Ettl J, Belleville E, Thill M, Fasching PA, Kolberg HC, Schulmeyer CE, Welslau M, Overkamp F, Tesch H, Fehm TN, Lüftner D, Schütz F, Wöckel A. Update Breast Cancer 2020 Part 3 - Early Breast Cancer. Geburtshilfe Frauenheilkd 2020; 80:1105-1114. [PMID: 33173238 PMCID: PMC7647721 DOI: 10.1055/a-1270-7208] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023] Open
Abstract
The treatment of patients with early breast cancer has always been characterised by escalation by new therapies and de-escalation through identification of better treatment regimens or introduction of better tools to estimate prognosis. Efforts in some of these areas in the last few years have led to solid data. The results of the large studies of de-escalation through use of multi-gene tests are available, as are the results of some studies that investigated the new anti-HER2 substances T-DM1 and pertuzumab in the early treatment situation. Several large-scale studies examining the role of CDK4/6 inhibitors will soon be concluded so innovations can be anticipated in this area also. This review article will summarise and classify the results of the latest publications.
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Affiliation(s)
- Jens Huober
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Andreas Schneeweiss
- National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Andreas D Hartkopf
- Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
| | - Volkmar Müller
- Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany
| | - Michael P Lux
- Klinik für Gynäkologie und Geburtshilfe, Frauenklinik St. Louise, Paderborn, St. Josefs-Krankenhaus, Salzkotten, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Johannes Ettl
- Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | | | - Marc Thill
- Agaplesion Markus Krankenhaus, Department of Gynecology and Gynecological Oncology, Frankfurt, Germany
| | - Peter A Fasching
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | | | - Carla E Schulmeyer
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | | | | | - Hans Tesch
- Oncology Practice at Bethanien Hospital Frankfurt, Frankfurt, Germany
| | - Tanja N Fehm
- Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Diana Lüftner
- Charité University Hospital, Department of Hematology, Oncology and Tumour Immunology, Berlin, Germany
| | - Florian Schütz
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
| | - Achim Wöckel
- Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
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25
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Fritsche LG, Patil S, Beesley LJ, VandeHaar P, Salvatore M, Ma Y, Peng RB, Taliun D, Zhou X, Mukherjee B. Cancer PRSweb: An Online Repository with Polygenic Risk Scores for Major Cancer Traits and Their Evaluation in Two Independent Biobanks. Am J Hum Genet 2020; 107:815-836. [PMID: 32991828 PMCID: PMC7675001 DOI: 10.1016/j.ajhg.2020.08.025] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 08/28/2020] [Indexed: 02/06/2023] Open
Abstract
To facilitate scientific collaboration on polygenic risk scores (PRSs) research, we created an extensive PRS online repository for 35 common cancer traits integrating freely available genome-wide association studies (GWASs) summary statistics from three sources: published GWASs, the NHGRI-EBI GWAS Catalog, and UK Biobank-based GWASs. Our framework condenses these summary statistics into PRSs using various approaches such as linkage disequilibrium pruning/p value thresholding (fixed or data-adaptively optimized thresholds) and penalized, genome-wide effect size weighting. We evaluated the PRSs in two biobanks: the Michigan Genomics Initiative (MGI), a longitudinal biorepository effort at Michigan Medicine, and the population-based UK Biobank (UKB). For each PRS construct, we provide measures on predictive performance and discrimination. Besides PRS evaluation, the Cancer-PRSweb platform features construct downloads and phenome-wide PRS association study results (PRS-PheWAS) for predictive PRSs. We expect this integrated platform to accelerate PRS-related cancer research.
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Affiliation(s)
- Lars G Fritsche
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Precision Health Data Science, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Snehal Patil
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Lauren J Beesley
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Precision Health Data Science, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Peter VandeHaar
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Maxwell Salvatore
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Precision Health Data Science, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Ying Ma
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Robert B Peng
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Precision Health Data Science, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Department of Statistics, Northwestern University, Evanston, IL 60208, USA
| | - Daniel Taliun
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Xiang Zhou
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Precision Health Data Science, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
| | - Bhramar Mukherjee
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Center for Precision Health Data Science, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Michigan Institute for Data Science, University of Michigan, Ann Arbor, MI 48109, USA; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
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26
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Tian J, Ying P, Ke J, Zhu Y, Yang Y, Gong Y, Zou D, Peng X, Yang N, Wang X, Mei S, Zhang Y, Wang C, Zhong R, Chang J, Miao X. ANKLE1 N 6 -Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability. Int J Cancer 2020; 146:3281-3293. [PMID: 31509622 DOI: 10.1002/ijc.32677] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 09/05/2019] [Indexed: 12/21/2022]
Abstract
The N6 -Methyladenosine (m6 A) modification plays an important role in many biological processes, especially tumor development. However, little is still known about how it affects colorectal cancer (CRC) carcinogenesis. Here, we first systematically investigate the association of variants related to m6 A modification with the CRC risk in 1,062 CRC cases and 2,184 controls by using our exome-wide association data and followed by two replication sets including 7,341 CRC cases and 7,902 controls. The variant rs8100241 located in ANKLE1 was significantly associated with CRC risk (odds ratio = 0.88, 95% confidence interval = 0.84-0.92, p = 4.85 × 10-8 ) in 8,403 cases and 10,086 controls. This variant was previously identified to be associated with the susceptibility of breast cancer with BRCA1 mutation triple negative breast cancer. Further functional analysis indicated that overexpression of the rs8100241[A] allele significantly increased the ANKLE1 m6 A level and facilitated the ANKLE1 protein expression compared to that of rs8100241[G] allele. We further found the ANKLE1 m6 A modification was catalyzed by the "writer" complex (METTL3, METTL14, or WTAP) and recognized by the "reader" YTHDF1. Mechanistically, we found that the ANKLE1 functions as a potential tumor suppressor that inhibits cell proliferation and facilitates the genomic stability. An elevated frequency of micronucleated cells, increased cell proliferation, and colony formation ability were observed when ANKLE1 knockdown. Our study illustrated that the germline missense variant can increase CRC risk by influencing ANKLE1 m6 A level, highlighting a clinical potential of variants-associated m6 A modification as a risk marker for CRC prevention.
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Affiliation(s)
- Jianbo Tian
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Pingting Ying
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Juntao Ke
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Ying Zhu
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yang Yang
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yajie Gong
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Danyi Zou
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiating Peng
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Nan Yang
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiaoyang Wang
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Shufang Mei
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yuxing Zhang
- Department of Colorectal Surgery, The Eighth Hospital of Wuhan City, Wuhan, China
| | - Changyi Wang
- Department of Non-Communicable Disease Prevention and Control, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, China
| | - Rong Zhong
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Jiang Chang
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiaoping Miao
- Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
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27
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Zhang H, Ahearn TU, Lecarpentier J, Barnes D, Beesley J, Qi G, Jiang X, O'Mara TA, Zhao N, Bolla MK, Dunning AM, Dennis J, Wang Q, Ful ZA, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Arun BK, Auer PL, Azzollini J, Barrowdale D, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bialkowska K, Blanco A, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Bondavalli D, Borg A, Brauch H, Brenner H, Briceno I, Broeks A, Brucker SY, Brüning T, Burwinkel B, Buys SS, Byers H, Caldés T, Caligo MA, Calvello M, Campa D, Castelao JE, Chang-Claude J, Chanock SJ, Christiaens M, Christiansen H, Chung WK, Claes KBM, Clarke CL, Cornelissen S, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Diez O, Domchek SM, Dörk T, Dwek M, Eccles DM, Ekici AB, Evans DG, Fasching PA, Figueroa J, Foretova L, Fostira F, Friedman E, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, García-Sáenz JA, Gaudet MM, Gayther SA, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel P, Häberle L, Hahnen E, Haiman CA, Hake CR, Hall P, Hamann U, Harkness EF, Heemskerk-Gerritsen BAM, Hillemanns P, et alZhang H, Ahearn TU, Lecarpentier J, Barnes D, Beesley J, Qi G, Jiang X, O'Mara TA, Zhao N, Bolla MK, Dunning AM, Dennis J, Wang Q, Ful ZA, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Arun BK, Auer PL, Azzollini J, Barrowdale D, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bialkowska K, Blanco A, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Bondavalli D, Borg A, Brauch H, Brenner H, Briceno I, Broeks A, Brucker SY, Brüning T, Burwinkel B, Buys SS, Byers H, Caldés T, Caligo MA, Calvello M, Campa D, Castelao JE, Chang-Claude J, Chanock SJ, Christiaens M, Christiansen H, Chung WK, Claes KBM, Clarke CL, Cornelissen S, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Diez O, Domchek SM, Dörk T, Dwek M, Eccles DM, Ekici AB, Evans DG, Fasching PA, Figueroa J, Foretova L, Fostira F, Friedman E, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, García-Sáenz JA, Gaudet MM, Gayther SA, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel P, Häberle L, Hahnen E, Haiman CA, Hake CR, Hall P, Hamann U, Harkness EF, Heemskerk-Gerritsen BAM, Hillemanns P, Hogervorst FBL, Holleczek B, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Howell A, Huebner H, Hulick PJ, Imyanitov EN, Isaacs C, Izatt L, Jager A, Jakimovska M, Jakubowska A, James P, Janavicius R, Janni W, John EM, Jones ME, Jung A, Kaaks R, Kapoor PM, Karlan BY, Keeman R, Khan S, Khusnutdinova E, Kitahara CM, Ko YD, Konstantopoulou I, Koppert LB, Koutros S, Kristensen VN, Laenkholm AV, Lambrechts D, Larsson SC, Laurent-Puig P, Lazaro C, Lazarova E, Lejbkowicz F, Leslie G, Lesueur F, Lindblom A, Lissowska J, Lo WY, Loud JT, Lubinski J, Lukomska A, MacInnis RJ, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martinez ME, Matricardi L, McGuffog L, McLean C, Mebirouk N, Meindl A, Menon U, Miller A, Mingazheva E, Montagna M, Mulligan AM, Mulot C, Muranen TA, Nathanson KL, Neuhausen SL, Nevanlinna H, Neven P, Newman WG, Nielsen FC, Nikitina-Zake L, Nodora J, Offit K, Olah E, Olopade OI, Olsson H, Orr N, Papi L, Papp J, Park-Simon TW, Parsons MT, Peissel B, Peixoto A, Peshkin B, Peterlongo P, Peto J, Phillips KA, Piedmonte M, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Prokofyeva D, Rack B, Radice P, Ramus SJ, Rantala J, Rashid MU, Rennert G, Rennert HS, Risch HA, Romero A, Rookus MA, Rübner M, Rüdiger T, Saloustros E, Sampson S, Sandler DP, Sawyer EJ, Scheuner MT, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schöttker B, Schürmann P, Senter L, Sharma P, Sherman ME, Shu XO, Singer CF, Smichkoska S, Soucy P, Southey MC, Spinelli JJ, Stone J, Stoppa-Lyonnet D, Swerdlow AJ, Szabo CI, Tamimi RM, Tapper WJ, Taylor JA, Teixeira MR, Terry M, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Troester MA, Truong T, Tung N, Untch M, Vachon CM, van den Ouweland AMW, van der Kolk LE, van Veen EM, vanRensburg EJ, Vega A, Wappenschmidt B, Weinberg CR, Weitzel JN, Wildiers H, Winqvist R, Wolk A, Yang XR, Yannoukakos D, Zheng W, Zorn KK, Milne RL, Kraft P, Simard J, Pharoah PDP, Michailidou K, Antoniou AC, Schmidt MK, Chenevix-Trench G, Easton DF, Chatterjee N, García-Closas M. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nat Genet 2020; 52:572-581. [PMID: 32424353 PMCID: PMC7808397 DOI: 10.1038/s41588-020-0609-2] [Show More Authors] [Citation(s) in RCA: 275] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 03/05/2020] [Indexed: 11/18/2022]
Abstract
Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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Affiliation(s)
- Haoyu Zhang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Thomas U Ahearn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA
| | - Julie Lecarpentier
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Daniel Barnes
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Jonathan Beesley
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Guanghao Qi
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Xia Jiang
- Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Tracy A O'Mara
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Ni Zhao
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Manjeet K Bolla
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Alison M Dunning
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Joe Dennis
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Qin Wang
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Zumuruda Abu Ful
- Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
| | - Kristiina Aittomäki
- Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Irene L Andrulis
- Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Hoda Anton-Culver
- Department of Epidemiology, Genetic Epidemiology Research Institute, University of California, Irvine, Irvine, CA, USA
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kristan J Aronson
- Department of Public Health Sciences and Cancer Research Institute, Queen's University, Kingston, Ontario, Canada
| | - Banu K Arun
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Paul L Auer
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
| | - Jacopo Azzollini
- Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
| | - Daniel Barrowdale
- Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
| | - Heiko Becher
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Matthias W Beckmann
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Sabine Behrens
- Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany
| | - Javier Benitez
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Marina Bermisheva
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia
| | - Katarzyna Bialkowska
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Ana Blanco
- Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saude (SERGAS), Santiago de Compostela, Spain
- CIBERER, Santiago de Compostela, Spain
| | - Carl Blomqvist
- Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Department of Oncology, Örebro University Hospital, Örebro, Sweden
| | - Natalia V Bogdanova
- N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
- Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
| | - Stig E Bojesen
- Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Bernardo Bonanni
- Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Davide Bondavalli
- Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Ake Borg
- Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden
| | - Hiltrud Brauch
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- iFIT Cluster of Excellence, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany
- Division of Preventive Oncology, DKFZ and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Ignacio Briceno
- Bioscience Department, Faculty of Medicine, Universidad de la Sabana, Chia, Colombia
| | - Annegien Broeks
- Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Sara Y Brucker
- Department of Women's Health, University of Tübingen, Tübingen, Germany
| | - Thomas Brüning
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Ruhr University Bochum, Bochum, Germany
| | - Barbara Burwinkel
- Molecular Epidemiology Group (C080), DKFZ, Heidelberg, Germany
- Molecular Biology of Breast Cancer, University Women's Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Saundra S Buys
- Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Helen Byers
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Trinidad Caldés
- Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Maria A Caligo
- Section of Molecular Genetics, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy
| | - Mariarosaria Calvello
- Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Daniele Campa
- Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany
- Department of Biology, University of Pisa, Pisa, Italy
| | - Jose E Castelao
- Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany
- Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA
| | - Melissa Christiaens
- Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
| | - Hans Christiansen
- Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
| | - Wendy K Chung
- Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA
| | | | - Christine L Clarke
- Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
| | - Sten Cornelissen
- Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Fergus J Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Angela Cox
- Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Simon S Cross
- Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
| | - Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Mary B Daly
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Peter Devilee
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Orland Diez
- Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Susan M Domchek
- Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Miriam Dwek
- Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK
| | - Diana M Eccles
- Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Arif B Ekici
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany
| | - D Gareth Evans
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Peter A Fasching
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
- David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jonine Figueroa
- Usher Institute of Population Health Sciences and Informatics, University of Edinburgh Medical School, Edinburgh, UK
| | - Lenka Foretova
- Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Florentia Fostira
- Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece
| | - Eitan Friedman
- The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Debra Frost
- Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
| | - Manuela Gago-Dominguez
- Genomic Medicine Group, Galician Foundation of Genomic Medicine, IDIS, Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Susan M Gapstur
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA
| | - Judy Garber
- Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA
| | - José A García-Sáenz
- Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Mia M Gaudet
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA
| | - Simon A Gayther
- Center for Bioinformatics and Functional Genomics and the Cedars-Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia
| | - Andrew K Godwin
- Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS, USA
| | - Mark S Goldberg
- Department of Medicine, McGill University, Montréal, Québec, Canada
- Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, Québec, Canada
- Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - David E Goldgar
- Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Anna González-Neira
- Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Mark H Greene
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Jacek Gronwald
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Pascal Guénel
- Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University of Paris-Saclay, Paris, France
| | - Lothar Häberle
- Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany
| | - Eric Hahnen
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Christopher A Haiman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Per Hall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Oncology, Södersjukhuset, Stockholm, Sweden
| | - Ute Hamann
- Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany
| | - Elaine F Harkness
- Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
- Nightingale Breast Screening Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK
| | | | - Peter Hillemanns
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Frans B L Hogervorst
- Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | | | - Antoinette Hollestelle
- Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Maartje J Hooning
- Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Robert N Hoover
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA
| | - John L Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Anthony Howell
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Hanna Huebner
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Peter J Hulick
- Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA
| | | | - Claudine Isaacs
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Louise Izatt
- Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Agnes Jager
- Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Milena Jakimovska
- Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia
| | - Anna Jakubowska
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
- Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland
| | - Paul James
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
| | - Ramunas Janavicius
- Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania
- State Research Institute Center for Innovative Medicine, Vilnius, Lithuania
| | - Wolfgang Janni
- Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Esther M John
- Department of Medicine, Division of Oncology, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, USA
| | - Michael E Jones
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Audrey Jung
- Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany
| | - Pooja Middha Kapoor
- Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany
- Faculty of Medicine, University of Heidelberg, Heidelberg, Germany
| | - Beth Y Karlan
- David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Renske Keeman
- Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Sofia Khan
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Elza Khusnutdinova
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia
- Department of Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa, Russia
| | - Cari M Kitahara
- Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Yon-Dschun Ko
- Department of Internal Medicine, Evangelische Kliniken Bonn, Johanniter Krankenhaus, Bonn, Germany
| | - Irene Konstantopoulou
- Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece
| | - Linetta B Koppert
- Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Stella Koutros
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA
| | - Vessela N Kristensen
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | | | - Diether Lambrechts
- VIB Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium
| | - Susanna C Larsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Conxi Lazaro
- Molecular Diagnostic Unit, Hereditary Cancer Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), CIBERONC, Barcelona, Spain
| | - Emilija Lazarova
- Ss. Cyril and Methodius University in Skopje, Medical Faculty, University Clinic of Radiotherapy and Oncology, Skopje, Republic of North Macedonia
| | - Flavio Lejbkowicz
- Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
| | - Goska Leslie
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | | | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Jolanta Lissowska
- Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center, Oncology Institute, Warsaw, Poland
| | - Wing-Yee Lo
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
- University of Tübingen, Tübingen, Germany
| | - Jennifer T Loud
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Jan Lubinski
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Alicja Lukomska
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Robert J MacInnis
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Arto Mannermaa
- Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland
- Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland
- Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland
| | | | - Siranoush Manoukian
- Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
| | - Sara Margolin
- Department of Oncology, Södersjukhuset, Stockholm, Sweden
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Maria Elena Martinez
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA
| | - Laura Matricardi
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Lesley McGuffog
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Catriona McLean
- Department of Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Noura Mebirouk
- Genetic Epidemiology of Cancer Team, INSERM U900, Institut Curie, PSL University, Mines ParisTech, Paris, France
| | - Alfons Meindl
- Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany
| | - Usha Menon
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK
| | - Austin Miller
- NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Elvira Mingazheva
- Department of Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa, Russia
| | - Marco Montagna
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy
| | - Anna Marie Mulligan
- Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Claire Mulot
- Université Paris Sorbonne Cité, INSERM UMR-S1147, Paris, France
| | - Taru A Muranen
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Katherine L Nathanson
- Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Susan L Neuhausen
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Heli Nevanlinna
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Patrick Neven
- Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
| | - William G Newman
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Finn C Nielsen
- Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Jesse Nodora
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Family Medicine and Public Health, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Kenneth Offit
- Clinical Genetics Research Laboratory, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Edith Olah
- Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
| | - Olufunmilayo I Olopade
- Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA
- Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia
| | - Håkan Olsson
- Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden
- Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nick Orr
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Laura Papi
- Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
| | - Janos Papp
- Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
| | | | - Michael T Parsons
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Bernard Peissel
- Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
| | - Ana Peixoto
- Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
| | - Beth Peshkin
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Paolo Peterlongo
- Genome Diagnostics Program, IFOM, FIRC Institute of Molecular Oncology, Milan, Italy
| | - Julian Peto
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Kelly-Anne Phillips
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
- Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - Marion Piedmonte
- NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Dijana Plaseska-Karanfilska
- Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia
| | - Karolina Prajzendanc
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Ross Prentice
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Darya Prokofyeva
- Department of Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa, Russia
| | - Brigitte Rack
- Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Paolo Radice
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, INT, Milan, Italy
| | - Susan J Ramus
- Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia
- School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, New South Wales, Australia
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | | | - Muhammad U Rashid
- Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany
- Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), Lahore, Pakistan
| | - Gad Rennert
- Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
| | - Hedy S Rennert
- Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
| | - Harvey A Risch
- Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Atocha Romero
- Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain
- Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal
| | - Matti A Rookus
- Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Matthias Rübner
- Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany
| | - Thomas Rüdiger
- Institute of Pathology, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | | | - Sarah Sampson
- Prevent Breast Cancer Centre and Nightingale Breast Screening Centre, Manchester University NHS Foundation Trust, Manchester, UK
| | - Dale P Sandler
- Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Durham, NC, USA
| | - Elinor J Sawyer
- Research Oncology, Guy's Hospital, King's College London, London, UK
| | - Maren T Scheuner
- Cancer Genetics and Prevention Program, University of California, San Francisco, San Francisco, CA, USA
| | - Rita K Schmutzler
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Andreas Schneeweiss
- Molecular Biology of Breast Cancer, University Women's Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany
- NCT, University Hospital and DKFZ, Heidelberg, Germany
| | - Minouk J Schoemaker
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter Schürmann
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Leigha Senter
- Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Priyanka Sharma
- Department of Internal Medicine, Division of Oncology, University of Kansas Medical Center, Westwood, Kansas City, KS, USA
| | - Mark E Sherman
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Jacksonville, FL, USA
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Christian F Singer
- Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Snezhana Smichkoska
- Ss. Cyril and Methodius University in Skopje, Medical Faculty, University Clinic of Radiotherapy and Oncology, Skopje, Republic of North Macedonia
| | - Penny Soucy
- Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, Québec, Canada
| | - Melissa C Southey
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia
| | - John J Spinelli
- Population Oncology, BC Cancer, Vancouver, British Columbia, Canada
- School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jennifer Stone
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
- Curtin UWA Centre for Genetic Origins of Health and Disease, Curtin University and University of Western Australia, Perth, Western Australia, Australia
| | - Dominique Stoppa-Lyonnet
- Department of Genetics, INSERM U830, Institut Curie, Paris Descartes Sorbonne-Paris Cité University, Paris, France
| | - Anthony J Swerdlow
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
- Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
| | - Csilla I Szabo
- National Human Genome Research Institute, National Cancer Institute, Bethesda, MD, USA
| | - Rulla M Tamimi
- Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | | | - Jack A Taylor
- Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Durham, NC, USA
- Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Durham, NC, USA
| | - Manuel R Teixeira
- Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
- Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal
| | - MaryBeth Terry
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Darcy L Thull
- Department of Medicine, Magee-Womens Hospital, School of Medicine, University of Pittsburgh , Pittsburgh, PA, USA
| | - Marc Tischkowitz
- Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, Québec, Canada
- Department of Medical Genetics, National Institute for Health Research, Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Amanda E Toland
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
| | - Rob A E M Tollenaar
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Ian Tomlinson
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Diana Torres
- Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany
- Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia
| | - Melissa A Troester
- Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Thérèse Truong
- Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University of Paris-Saclay, Paris, France
| | - Nadine Tung
- Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Michael Untch
- Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany
| | - Celine M Vachon
- Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
| | | | - Lizet E van der Kolk
- Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Elke M van Veen
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | | | - Ana Vega
- Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saude (SERGAS), Santiago de Compostela, Spain
- CIBERER, Santiago de Compostela, Spain
| | - Barbara Wappenschmidt
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Clarice R Weinberg
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Durham, NC, USA
| | | | - Hans Wildiers
- Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
| | - Robert Winqvist
- Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland
- Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Alicja Wolk
- Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Xiaohong R Yang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA
| | - Drakoulis Yannoukakos
- Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Kristin K Zorn
- Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia
| | - Peter Kraft
- Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Jacques Simard
- Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, Québec, Canada
| | - Paul D P Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Kyriaki Michailidou
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
- Cyprus School of Molecular Medicine, Nicosia, Cyprus
| | - Antonis C Antoniou
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Marjanka K Schmidt
- Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
- Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Georgia Chenevix-Trench
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Douglas F Easton
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Nilanjan Chatterjee
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
- Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
| | - Montserrat García-Closas
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA
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Adamson AW, Ding YC, Mendez-Dorantes C, Bailis AM, Stark JM, Neuhausen SL. The RAD52 S346X variant reduces risk of developing breast cancer in carriers of pathogenic germline BRCA2 mutations. Mol Oncol 2020; 14:1124-1133. [PMID: 32175645 PMCID: PMC7266271 DOI: 10.1002/1878-0261.12665] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 02/25/2020] [Accepted: 03/10/2020] [Indexed: 01/16/2023] Open
Abstract
Women who carry pathogenic mutations in BRCA1 and BRCA2 have a lifetime risk of developing breast cancer of up to 80%. However, risk estimates vary in part due to genetic modifiers. We investigated the association of the RAD52 S346X variant as a modifier of the risk of developing breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. The RAD52 S346X allele was associated with a reduced risk of developing breast cancer in BRCA2 carriers [per‐allele hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.56–0.86; P = 0.0008] and to a lesser extent in BRCA1 carriers (per‐allele HR = 0.78, 95% CI 0.64–0.97, P = 0.02). We examined how this variant affected DNA repair. Using a reporter system that measures repair of DNA double‐strand breaks (DSBs) by single‐strand annealing (SSA), expression of hRAD52 suppressed the loss of this repair in Rad52−/− mouse embryonic stem cells. When hRAD52 S346X was expressed in these cells, there was a significantly reduced frequency of SSA. Interestingly, expression of hRAD52 S346X also reduced the stimulation of SSA observed upon depletion of BRCA2, demonstrating the reciprocal roles for RAD52 and BRCA2 in the control of DSB repair by SSA. From an immunofluorescence analysis, we observed little nuclear localization of the mutant protein as compared to the wild‐type; it is likely that the reduced nuclear levels of RAD52 S346X explain the diminished DSB repair by SSA. Altogether, we identified a genetic modifier that protects against breast cancer in women who carry pathogenic mutations in BRCA2 (P = 0.0008) and to a lesser extent BRCA1 (P = 0.02). This RAD52 mutation causes a reduction in DSB repair by SSA, suggesting that defects in RAD52‐dependent DSB repair are linked to reduced tumor risk in BRCA2‐mutation carriers.
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Affiliation(s)
- Aaron W Adamson
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Yuan Chun Ding
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Carlos Mendez-Dorantes
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Adam M Bailis
- College of Health Professions, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jeremy M Stark
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Susan L Neuhausen
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
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29
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Schneeweiss A, Hartkopf AD, Müller V, Wöckel A, Lux MP, Janni W, Ettl J, Belleville E, Huober J, Thill M, Fasching PA, Kolberg HC, Pöschke P, Welslau M, Overkamp F, Tesch H, Fehm TN, Lüftner D, Schütz F. Update Breast Cancer 2020 Part 1 - Early Breast Cancer: Consolidation of Knowledge About Known Therapies. Geburtshilfe Frauenheilkd 2020; 80:277-287. [PMID: 32139917 PMCID: PMC7056401 DOI: 10.1055/a-1111-2431] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/03/2020] [Accepted: 02/03/2020] [Indexed: 02/08/2023] Open
Abstract
This review is intended to present the latest developments in the prevention and treatment of early breast cancer. The risk of breast cancer can be increasingly better characterised with large epidemiological studies on genetic and non-genetic risk factors. Through new analyses, the evidence for high-penetrance genes as well as for low-penetrance genes was able to be improved. New data on denosumab and atezolizumab are available in the neoadjuvant situation as is a pooled appraisal of numerous studies on capecitabine in the curative situation. There is also an update to the overall survival data of pertuzumab in the adjuvant situation with a longer follow-up observation period. Finally, digital medicine is steadily finding its way into science. A recently conducted study on automated breast cancer detection using artificial intelligence establishes the basis for a future review in clinical studies.
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Affiliation(s)
- Andreas Schneeweiss
- National Center for Tumor Diseases, Division Gynecologic Oncology, University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Andreas D. Hartkopf
- Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
| | - Volkmar Müller
- Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany
| | - Achim Wöckel
- Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
| | - Michael P. Lux
- Klinik für Gynäkologie und Geburtshilfe, Frauenklinik St. Louise, Paderborn, St. Josefs-Krankenhaus, Salzkotten, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Johannes Ettl
- Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | | | - Jens Huober
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Marc Thill
- Agaplesion Markus Krankenhaus, Frauenklinik, Frankfurt, Germany
| | - Peter A. Fasching
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | | | - Patrik Pöschke
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | | | | | - Hans Tesch
- Oncology Practice at Bethanien Hospital Frankfurt, Frankfurt, Germany
| | - Tanja N. Fehm
- Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Diana Lüftner
- Charité University Hospital, Campus Benjamin Franklin, Department of Hematology, Oncology and Tumour Immunology, Berlin, Germany
| | - Florian Schütz
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
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30
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Lee S, Liang X, Woods M, Reiner AS, Concannon P, Bernstein L, Lynch CF, Boice JD, Deasy JO, Bernstein JL, Oh JH. Machine learning on genome-wide association studies to predict the risk of radiation-associated contralateral breast cancer in the WECARE Study. PLoS One 2020; 15:e0226157. [PMID: 32106268 PMCID: PMC7046218 DOI: 10.1371/journal.pone.0226157] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 11/20/2019] [Indexed: 01/13/2023] Open
Abstract
The purpose of this study was to identify germline single nucleotide polymorphisms (SNPs) that optimally predict radiation-associated contralateral breast cancer (RCBC) and to provide new biological insights into the carcinogenic process. Fifty-two women with contralateral breast cancer and 153 women with unilateral breast cancer were identified within the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study who were at increased risk of RCBC because they were ≤ 40 years of age at first diagnosis of breast cancer and received a scatter radiation dose > 1 Gy to the contralateral breast. A previously reported algorithm, preconditioned random forest regression, was applied to predict the risk of developing RCBC. The resulting model produced an area under the curve (AUC) of 0.62 (p = 0.04) on hold-out validation data. The biological analysis identified the cyclic AMP-mediated signaling and Ephrin-A as significant biological correlates, which were previously shown to influence cell survival after radiation in an ATM-dependent manner. The key connected genes and proteins that are identified in this analysis were previously identified as relevant to breast cancer, radiation response, or both. In summary, machine learning/bioinformatics methods applied to genome-wide genotyping data have great potential to reveal plausible biological correlates associated with the risk of RCBC.
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Affiliation(s)
- Sangkyu Lee
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Xiaolin Liang
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Meghan Woods
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Anne S. Reiner
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Patrick Concannon
- Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, United States of America
| | - Leslie Bernstein
- Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, United States of America
| | - Charles F. Lynch
- Department of Epidemiology, The University of Iowa, Iowa City, IA, United States of America
| | - John D. Boice
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America
| | - Joseph O. Deasy
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Jonine L. Bernstein
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Jung Hun Oh
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
- * E-mail:
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31
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Jacinta-Fernandes A, Xavier JM, Magno R, Lage JG, Maia AT. Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk. NPJ Genom Med 2020; 5:4. [PMID: 32128252 PMCID: PMC7018948 DOI: 10.1038/s41525-019-0112-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 12/05/2019] [Indexed: 12/15/2022] Open
Abstract
Most breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms-TargetScan and miRanda-to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ( P ≤ 5 × 10 - 8 ) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3'-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and reinforce the role of miRNA-mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.
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Affiliation(s)
- Ana Jacinta-Fernandes
- 1Department of Biomedical Sciences and Medicine (DCBM), Universidade do Algarve, Faro, 8005-139 Portugal.,2Centre for Biomedical Research (CBMR), Universidade do Algarve, Faro, 8005-139 Portugal.,3Algarve Biomedical Center (ABC), Universidade do Algarve, Faro, 8005-139 Portugal
| | - Joana M Xavier
- 1Department of Biomedical Sciences and Medicine (DCBM), Universidade do Algarve, Faro, 8005-139 Portugal.,2Centre for Biomedical Research (CBMR), Universidade do Algarve, Faro, 8005-139 Portugal.,3Algarve Biomedical Center (ABC), Universidade do Algarve, Faro, 8005-139 Portugal
| | - Ramiro Magno
- 2Centre for Biomedical Research (CBMR), Universidade do Algarve, Faro, 8005-139 Portugal.,3Algarve Biomedical Center (ABC), Universidade do Algarve, Faro, 8005-139 Portugal
| | - Joel G Lage
- 1Department of Biomedical Sciences and Medicine (DCBM), Universidade do Algarve, Faro, 8005-139 Portugal.,2Centre for Biomedical Research (CBMR), Universidade do Algarve, Faro, 8005-139 Portugal.,3Algarve Biomedical Center (ABC), Universidade do Algarve, Faro, 8005-139 Portugal
| | - Ana-Teresa Maia
- 1Department of Biomedical Sciences and Medicine (DCBM), Universidade do Algarve, Faro, 8005-139 Portugal.,2Centre for Biomedical Research (CBMR), Universidade do Algarve, Faro, 8005-139 Portugal.,3Algarve Biomedical Center (ABC), Universidade do Algarve, Faro, 8005-139 Portugal
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32
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Identification of two novel breast cancer loci through large-scale genome-wide association study in the Japanese population. Sci Rep 2019; 9:17332. [PMID: 31757997 PMCID: PMC6874604 DOI: 10.1038/s41598-019-53654-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 10/26/2019] [Indexed: 12/21/2022] Open
Abstract
Genome-wide association studies (GWAS) have successfully identified about 70 genomic loci associated with breast cancer. Owing to the complexity of linkage disequilibrium and environmental exposures in different populations, it is essential to perform regional GWAS for better risk prediction. This study aimed to investigate the genetic architecture and to assess common genetic risk model of breast cancer with 6,669 breast cancer patients and 21,930 female controls in the Japanese population. This GWAS identified 11 genomic loci that surpass genome-wide significance threshold of P < 5.0 × 10−8 with nine previously reported loci and two novel loci that include rs9862599 on 3q13.11 (ALCAM) and rs75286142 on 21q22.12 (CLIC6-RUNX1). Validation study was carried out with 981 breast cancer cases and 1,394 controls from the Aichi Cancer Center. Pathway analyses of GWAS signals identified association of dopamine receptor medicated signaling and protein amino acid deacetylation with breast cancer. Weighted genetic risk score showed that individuals who were categorized in the highest risk group are approximately 3.7 times more likely to develop breast cancer compared to individuals in the lowest risk group. This well-powered GWAS is a representative study to identify SNPs that are associated with breast cancer in the Japanese population.
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33
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Sepahi I, Faust U, Sturm M, Bosse K, Kehrer M, Heinrich T, Grundman-Hauser K, Bauer P, Ossowski S, Susak H, Varon R, Schröck E, Niederacher D, Auber B, Sutter C, Arnold N, Hahnen E, Dworniczak B, Wang-Gorke S, Gehrig A, Weber BHF, Engel C, Lemke JR, Hartkopf A, Nguyen HP, Riess O, Schroeder C. Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women. BMC Cancer 2019; 19:787. [PMID: 31395037 PMCID: PMC6686546 DOI: 10.1186/s12885-019-5946-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 07/16/2019] [Indexed: 01/22/2023] Open
Abstract
Background Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon. Methods We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways. Results Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00–27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05. Conclusions To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results. Electronic supplementary material The online version of this article (10.1186/s12885-019-5946-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ilnaz Sepahi
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Ulrike Faust
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Marc Sturm
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Kristin Bosse
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Martin Kehrer
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Tilman Heinrich
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Kathrin Grundman-Hauser
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Peter Bauer
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.,CENTOGENE AG, Rostock, Germany
| | - Stephan Ossowski
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Hana Susak
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Raymonda Varon
- Institute of Medical and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | - Dieter Niederacher
- Department of Obstetrics and Gynaecology, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Bernd Auber
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Christian Sutter
- Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
| | - Norbert Arnold
- Department of Gynaecology and Obstetrics and Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Eric Hahnen
- Centre for Hereditary Breast and Ovarian Cancer, University of Cologne and University Hospital Cologne, Cologne, Germany
| | - Bernd Dworniczak
- Institute of Human Genetics, University Hospital Münster, Münster, Germany
| | - Shan Wang-Gorke
- Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Andrea Gehrig
- Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany
| | - Bernhard H F Weber
- Institute of Human Genetics, University of Regensburg, Regensburg, Germany
| | - Christoph Engel
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
| | - Johannes R Lemke
- Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany
| | - Andreas Hartkopf
- Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany
| | - Huu Phuc Nguyen
- Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany
| | - Olaf Riess
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Christopher Schroeder
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
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Ellsworth DL, Turner CE, Ellsworth RE. A Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci, and the Role of Nontraditional Genetic Elements. JOURNAL OF ONCOLOGY 2019; 2019:4382606. [PMID: 31379942 PMCID: PMC6652078 DOI: 10.1155/2019/4382606] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 06/23/2019] [Indexed: 12/31/2022]
Abstract
Triple negative breast cancer (TNBC), representing 10-15% of breast tumors diagnosed each year, is a clinically defined subtype of breast cancer associated with poor prognosis. The higher incidence of TNBC in certain populations such as young women and/or women of African ancestry and a unique pathological phenotype shared between TNBC and BRCA1-deficient tumors suggest that TNBC may be inherited through germline mutations. In this article, we describe genes and genetic elements, beyond BRCA1 and BRCA2, which have been associated with increased risk of TNBC. Multigene panel testing has identified high- and moderate-penetrance cancer predisposition genes associated with increased risk for TNBC. Development of large-scale genome-wide SNP assays coupled with genome-wide association studies (GWAS) has led to the discovery of low-penetrance TNBC-associated loci. Next-generation sequencing has identified variants in noncoding RNAs, viral integration sites, and genes in underexplored regions of the human genome that may contribute to the genetic underpinnings of TNBC. Advances in our understanding of the genetics of TNBC are driving improvements in risk assessment and patient management.
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Affiliation(s)
| | - Clesson E. Turner
- Murtha Cancer Center/Research Program, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Rachel E. Ellsworth
- Murtha Cancer Center/Research Program, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, USA
- Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
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Rath M, Li Q, Li H, Lindström S, Miron A, Miron P, Dowton AE, Meyer ME, Larson BG, Pomerantz M, Seo JH, Collins LC, Vardeh H, Brachtel E, Come SE, Borges V, Schapira L, Tamimi RM, Partridge AH, Freedman M, Ruddy KJ. Evaluation of significant genome-wide association studies risk - SNPs in young breast cancer patients. PLoS One 2019; 14:e0216997. [PMID: 31125336 PMCID: PMC6534300 DOI: 10.1371/journal.pone.0216997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 05/02/2019] [Indexed: 02/06/2023] Open
Abstract
Purpose Genome-wide-association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer. Most of these studies were conducted primarily in postmenopausal breast cancer patients. Therefore, we set out to assess whether or not these breast cancer variants are also associated with an elevated risk of breast cancer in young premenopausal patients. Methods In 451 women of European ancestry who had prospectively enrolled in a longitudinal cohort study for women diagnosed with breast cancer at or under age 40, we genotyped 44 SNPs that were previously associated with breast cancer risk. A control group was comprised of 1142 postmenopausal healthy women from the Nurses’ Health Study (NHS). We assessed if the frequencies of the adequately genotyped SNPs differed significantly (p≤0.05) between the cohort of young breast cancer patients and postmenopausal controls, and then we corrected for multiple testing. Results Genotyping of the controls or cases was inadequate for comparisons between the groups for seven of the 44 SNPs. 9 of the remaining 37 were associated with breast cancer risk in young women with a p-value <0.05: rs10510102, rs1219648, rs13387042, rs1876206, rs2936870, rs2981579, rs3734805, rs3803662 and rs4973768. The directions of these associations were consistent with those in postmenopausal women. However, after correction for multiple testing (Benjamini Hochberg) none of the results remained statistically significant. Conclusion After correction for multiple testing, none of the alleles for postmenopausal breast cancer were clearly associated with risk of premenopausal breast cancer in this relatively small study.
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Affiliation(s)
- Michelle Rath
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
| | - Qiyuan Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
- National Engineering Research Center for Biochip, Shanghai Biochip Limited Corporation, Shanghai, China
| | - Huili Li
- National Engineering Research Center for Biochip, Shanghai Biochip Limited Corporation, Shanghai, China
| | - Sara Lindström
- Department of Epidemiology, University of Washington, Seattle, United States of America
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States of America
| | - Alexander Miron
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States of America
| | - Penelope Miron
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States of America
| | - Anne E. Dowton
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
| | - Meghan E. Meyer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
| | - Bryce G. Larson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
| | - Mark Pomerantz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
| | - Ji-Heui Seo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
| | - Laura C. Collins
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America
| | - Hilde Vardeh
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America
| | - Elena Brachtel
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America
| | - Steven E. Come
- Beth Israel Deaconess Medical Center, Boston, United States of America
| | - Virginia Borges
- University of Colorado Denver, Aurora, United States of America
| | - Lidia Schapira
- Stanford University Medical Center, Palo Alto, United States of America
| | - Rulla M. Tamimi
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, United States of America
| | - Ann H. Partridge
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
| | - Matthew Freedman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America
| | - Kathryn J. Ruddy
- Department of Oncology, Mayo Clinic, Rochester, United States of America
- * E-mail:
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Huo D, Hu H, Rhie SK, Gamazon ER, Cherniack AD, Liu J, Yoshimatsu TF, Pitt JJ, Hoadley KA, Troester M, Ru Y, Lichtenberg T, Sturtz LA, Shelley CS, Benz CC, Mills GB, Laird PW, Shriver CD, Perou CM, Olopade OI. Comparison of Breast Cancer Molecular Features and Survival by African and European Ancestry in The Cancer Genome Atlas. JAMA Oncol 2019; 3:1654-1662. [PMID: 28472234 DOI: 10.1001/jamaoncol.2017.0595] [Citation(s) in RCA: 211] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Importance African Americans have the highest breast cancer mortality rate. Although racial difference in the distribution of intrinsic subtypes of breast cancer is known, it is unclear if there are other inherent genomic differences that contribute to the survival disparities. Objectives To investigate racial differences in breast cancer molecular features and survival and to estimate the heritability of breast cancer subtypes. Design, Setting, and Participants Among a convenience cohort of patients with invasive breast cancer, breast tumor and matched normal tissue sample data (as of September 18, 2015) were obtained from The Cancer Genome Atlas. Main Outcomes and Measures Breast cancer–free interval, tumor molecular features, and genetic variants. Results Participants were 930 patients with breast cancer, including 154 black patients of African ancestry (mean [SD] age at diagnosis, 55.66 [13.01] years; 98.1% [n = 151] female) and 776 white patients of European ancestry (mean [SD] age at diagnosis, 59.51 [13.11] years; 99.0% [n = 768] female). Compared with white patients, black patients had a worse breast cancer-free interval (hazard ratio, HR=1.67; 95% CI, 1.02-2.74; P = .043). They had a higher likelihood of basal-like (odds ratio, 3.80; 95% CI, 2.46-5.87; P < .001) and human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])–enriched (odds ratio, 2.22; 95% CI, 1.10-4.47; P = .027) breast cancer subtypes, with the Luminal A subtype as the reference. Blacks had more TP53 mutations and fewer PIK3CA mutations than whites. While most molecular differences were eliminated after adjusting for intrinsic subtype, the study found 16 DNA methylation probes, 4 DNA copy number segments, 1 protein, and 142 genes that were differentially expressed, with the gene-based signature having an excellent capacity for distinguishing breast tumors from black vs white patients (cross-validation C index, 0.878). Using germline genotypes, the heritability of breast cancer subtypes (basal vs nonbasal) was estimated to be 0.436 (P = 1.5 × 10−14). The estrogen receptor–positive polygenic risk score built from 89 known susceptibility variants was higher in blacks than in whites (difference, 0.24; P = 2.3 × 10−5), while the estrogen receptor–negative polygenic risk score was much higher in blacks than in whites (difference, 0.48; P = 2.8 × 10−11). Conclusions and Relevance On the molecular level, after adjusting for intrinsic subtype frequency differences, this study found a modest number of genomic differences but a significant clinical survival outcome difference between blacks and whites in The Cancer Genome Atlas data set. Moreover, more than 40% of breast cancer subtype frequency differences could be explained by genetic variants. These data could form the basis for the development of molecular targeted therapies to improve clinical outcomes for the specific subtypes of breast cancers that disproportionately affect black women. Findings also indicate that personalized risk assessment and optimal treatment could reduce deaths from aggressive breast cancers for black women.
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Affiliation(s)
- Dezheng Huo
- Department of Public Health Sciences, The University of Chicago, Chicago, Illinois,Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Hai Hu
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, Pennsylvania
| | - Suhn K Rhie
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles
| | - Eric R Gamazon
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee
| | - Andrew D Cherniack
- The Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Jianfang Liu
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, Pennsylvania
| | - Toshio F Yoshimatsu
- Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Jason J Pitt
- Committee of Genetics, Genomics, and Systems Biology, The University of Chicago, Chicago, Illinois
| | - Katherine A Hoadley
- Department of Genetics and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill
| | - Melissa Troester
- Department of Epidemiology, The University of North Carolina at Chapel Hill
| | - Yuanbin Ru
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, Pennsylvania
| | - Tara Lichtenberg
- The Research Institute, Nationwide Children’s Hospital, Columbus, Ohio
| | - Lori A Sturtz
- Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, Pennsylvania
| | - Carl S Shelley
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison
| | | | - Gordon B Mills
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston
| | - Peter W Laird
- Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan
| | - Craig D Shriver
- Clinical Breast Care Project, Murtha Cancer Center, Walter Reed National Military Medical Center/Uniformed Services University of the Health Sciences, Bethesda, Maryland
| | - Charles M Perou
- Department of Genetics and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill
| | - Olufunmilayo I Olopade
- Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois,Committee of Genetics, Genomics, and Systems Biology, The University of Chicago, Chicago, Illinois
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Hartkopf AD, Müller V, Wöckel A, Lux MP, Janni W, Nabieva N, Taran FA, Ettl J, Lüftner D, Belleville E, Schütz F, Fasching PA, Fehm TN, Kolberg HC, Overkamp F, Schneeweiss A, Tesch H. Update Breast Cancer 2019 Part 1 - Implementation of Study Results of Novel Study Designs in Clinical Practice in Patients with Early Breast Cancer. Geburtshilfe Frauenheilkd 2019; 79:256-267. [PMID: 30880824 PMCID: PMC6414304 DOI: 10.1055/a-0842-6614] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 01/28/2019] [Indexed: 12/18/2022] Open
Abstract
For many years, small but significant advancements have been made time and again in the prevention and treatment of early breast cancer. The so-called panel gene analyses are becoming more and more important in prevention, since the risk due to the tested genes is better understood and as a result, concepts for integration in health care can be developed. In the adjuvant situation, the first study in the so-called post-neoadjuvant situation was able to demonstrate a clear improvement in the prognosis with an absent pathological complete remission following trastuzumab or pertuzumab + trastuzumab. Additional studies with this post-neoadjuvant therapeutic concept are still being conducted at present. The CDK4/6 inhibitors which had shown a significant improvement in progression-free survival in a metastatic situation are currently being tested in the adjuvant situation in large therapeutic studies. These and other new data for the treatment or prevention of primary breast cancer are presented in this review against the backdrop of current studies.
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Affiliation(s)
- Andreas D. Hartkopf
- Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
| | - Volkmar Müller
- Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany
| | - Achim Wöckel
- Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
| | - Michael P. Lux
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Naiba Nabieva
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Florin-Andrei Taran
- Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
| | - Johannes Ettl
- Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Diana Lüftner
- Charité University Hospital, Campus Benjamin Franklin, Department of Hematology, Oncology and Tumour Immunology, Berlin, Germany
| | | | - Florian Schütz
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
| | - Peter A. Fasching
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Tanja N. Fehm
- Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany
| | | | | | - Andreas Schneeweiss
- National Center for Tumor Diseases, Division Gynecologic Oncology, University Hospital Heidelberg, Heidelberg, Germany
| | - Hans Tesch
- Oncology Practice at Bethanien Hospital Frankfurt, Frankfurt, Germany
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Zavala VA, Serrano-Gomez SJ, Dutil J, Fejerman L. Genetic Epidemiology of Breast Cancer in Latin America. Genes (Basel) 2019; 10:E153. [PMID: 30781715 PMCID: PMC6410045 DOI: 10.3390/genes10020153] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 02/13/2019] [Accepted: 02/14/2019] [Indexed: 12/20/2022] Open
Abstract
The last 10 years witnessed an acceleration of our understanding of what genetic factors underpin the risk of breast cancer. Rare high- and moderate-penetrance variants such as those in the BRCA genes account for a small proportion of the familial risk of breast cancer. Low-penetrance alleles are expected to underlie the remaining heritability. By now, there are about 180 genetic polymorphisms that are associated with risk, most of them of modest effect. In combination, they can be used to identify women at the lowest or highest ends of the risk spectrum, which might lead to more efficient cancer prevention strategies. Most of these variants were discovered in populations of European descent. As a result, we might be failing to discover additional polymorphisms that could explain risk in other groups. This review highlights breast cancer genetic epidemiology studies conducted in Latin America, and summarizes the information that they provide, with special attention to similarities and differences with studies in other populations. It includes studies of common variants, as well as moderate- and high-penetrance variants. In addition, it addresses the gaps that need to be bridged in order to better understand breast cancer genetic risk in Latin America.
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Affiliation(s)
- Valentina A Zavala
- Department of Medicine, Division of General Internal Medicine, University of California San Francisco, San Francisco, CA 94143-1793, USA.
| | - Silvia J Serrano-Gomez
- Grupo de investigación en biología del cáncer, Instituto Nacional de Cancerología, Bogotá 11001000, Colombia.
| | - Julie Dutil
- Cancer Biology Division, Ponce Research Institute, Ponce Health Sciences University, Ponce, PR 00732, USA.
| | - Laura Fejerman
- Department of Medicine, Division of General Internal Medicine, University of California San Francisco, San Francisco, CA 94143-1793, USA.
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Wendt C, Margolin S. Identifying breast cancer susceptibility genes - a review of the genetic background in familial breast cancer. Acta Oncol 2019; 58:135-146. [PMID: 30606073 DOI: 10.1080/0284186x.2018.1529428] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Heritage is the most important risk factor for breast cancer. About 15-20% of breast cancer is familial, referring to affected women who have one or more first- or second-degree relatives with the disease. The heritable component in these families is substantial, especially in families with aggregation of breast cancer with low age at onset. Identifying breast cancer susceptibility genes: Since the discovery of the highly penetrant autosomal dominant susceptibility genes BRCA1 and BRCA2 in the 1990s, several more breast cancer genes that confer a moderate to high risk of breast cancer have been identified. Furthermore, during the last decade, advances in genomic technologies have led to large scale genotyping in genome-wide association studies that have identified a considerable amount of common low penetrance loci. In total, the high risk genes, BRCA1, BRCA2, TP53, STK11, CD1 and PTEN account for approximately 20% of the familial risk. Moderate risk variants account for up to 5% of the inherited familial risk. The more than 180 identified low-risk loci explain 18% of the familial risk. Altogether more than half of the genetic background in familial breast cancer remains unclear. Other genes and low risk loci that explain a part the remaining fraction will probably be identified. Clinical aspects and future perspectives: Definitive clinical recommendations can be drawn only for carriers of germline variants in a limited number of high and moderate risk genes for which an association with breast cancer has been established. Future progress in evaluating previously identified breast cancer candidate variants and low risk loci as well as exploring new ones can play an important role in improving individual risk prediction in familial breast cancer.
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Affiliation(s)
- Camilla Wendt
- Department of Oncology, Södersjukhuset, Stockholm, Sweden
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Sara Margolin
- Department of Oncology, Södersjukhuset, Stockholm, Sweden
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
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40
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Torres D, Lorenzo Bermejo J, Garcia Mesa K, Gilbert M, Briceño I, Pohl-Zeidler S, González Silos R, Boekstegers F, Plass C, Hamann U. Interaction between genetic ancestry and common breast cancer susceptibility variants in Colombian women. Int J Cancer 2019; 144:2181-2191. [PMID: 30485434 DOI: 10.1002/ijc.32023] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 11/05/2018] [Indexed: 01/31/2023]
Abstract
Latino women show lower incidences of breast cancer (BC) than non-Hispanic whites. Large-scale genetic association studies have identified variants robustly associated with BC risk in European women. We examine here the relevance of these variants to Colombian BC and possible interactions with genetic ancestry. Native American, European and African proportions were estimated for 1022 Colombian BC cases and 1023 controls. Logistic regression was applied to assess the association between 78 variants and BC risk and interactions between the variants and ancestry proportions. We constructed a multifactorial risk score combining established BC risk factors, associated risk variants and individual ancestry proportions. Each 1% increase in the Native American proportion translated into a 2.2% lower BC risk (95% CI: 1.4-2.9). Thirteen variants were associated with BC in Colombian women, with allele frequencies and risk effects partially different from European women. Ancestry proportions moderated the risk effects of two variants. The ability of Native American proportions to separate Colombian cases and controls (area-under-the-curve (AUC) = 0.61) was similar to the discriminative ability of family history of BC in first-degree female relatives (AUC = 0.58) or the combined effect of all 13 associated risk variants (AUC = 0.57). Our findings demonstrate ample potential for individualized BC prevention in Hispanic women taking advantage of individual Native American proportions, information on established susceptibility factors and recently identified common risk variants.
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Affiliation(s)
- Diana Torres
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia
| | - Justo Lorenzo Bermejo
- Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Karen Garcia Mesa
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Michael Gilbert
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ignacio Briceño
- Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.,Universidad de la Sabana, Bogota, Colombia
| | - Svenja Pohl-Zeidler
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rosa González Silos
- Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Felix Boekstegers
- Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Christoph Plass
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ute Hamann
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
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41
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Association between breast cancer risk factors and molecular type in postmenopausal patients with hormone receptor-positive early breast cancer. Breast Cancer Res Treat 2019; 174:453-461. [PMID: 30603996 DOI: 10.1007/s10549-018-05115-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 12/20/2018] [Indexed: 12/17/2022]
Abstract
PURPOSE Evidence shows that genetic and non-genetic risk factors for breast cancer (BC) differ relative to the molecular subtype. This analysis aimed to investigate associations between epidemiological risk factors and immunohistochemical subtypes in a cohort of postmenopausal, hormone receptor-positive BC patients. METHODS The prospective, single-arm, multicenter phase IV PreFace study (Evaluation of Predictive Factors Regarding the Effectivity of Aromatase Inhibitor Therapy) included 3529 postmenopausal patients with hormone receptor-positive early BC. Data on their epidemiological risk factors were obtained from patients' diaries and their medical histories. Data on estrogen receptor, progesterone receptor, and HER2 receptor status were obtained from pathology reports. Patients with incomplete information were excluded. Data were analyzed using conditional inference regression analysis, analysis of variance, and the chi-squared test. RESULTS In a cohort of 3392 patients, the strongest association with the molecular subtypes of BC was found for hormone replacement therapy (HRT) before diagnosis of early BC. The analysis showed that patients who took HRT at diagnosis had luminal A-like BC more often (83.7%) than those who had never taken HRT or had stopped taking it (75.5%). Luminal B-like BC and HER2-positive BC were diagnosed more often in women who had never taken HRT or had stopped taking it (13.3% and 11.2%, respectively) than in women who were taking HRT at diagnosis of BC (8.3% and 8.0%, respectively). CONCLUSIONS This analysis shows an association between HRT and the distribution of molecular subtypes of BC. However, no associations between other factors (e.g., age at diagnosis, body mass index, smoking status, age at menopause, number of deliveries, age at first delivery, breastfeeding history, or family history) were noted.
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42
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Downs B, Sherman S, Cui J, Kim YC, Snyder C, Christensen M, Luo J, Lynch H, Wang SM. Common genetic variants contribute to incomplete penetrance: evidence from cancer-free BRCA1 mutation carriers. Eur J Cancer 2018; 107:68-78. [PMID: 30551077 DOI: 10.1016/j.ejca.2018.10.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 10/25/2018] [Accepted: 10/31/2018] [Indexed: 10/27/2022]
Abstract
PURPOSE The presence of pathogenic germline mutation in BRCA1 gene is considered as the most penetrant genetic predisposition for breast cancer. However, a portion of BRCA1 mutation carriers never develops breast cancer throughout their lifetime. This phenomenon is called incomplete penetrance. Genetic factor is proposed to contribute to this phenomenon, but the details regarding the genetic factor remain elusive. BRCA1 mutations were inherited from the ancestors of the mutation carrier families during human evolution, and their presence is a consistent threat to the survival of the mutation carrier population. In the present study, we hypothesize that evolution could positively select genetic components in the mutation carrier population to suppress the oncogenesis imposed by the predisposition. EXPERIMENTAL DESIGN To test our hypothesis, we used whole exome sequencing to compare germline variation of all genes in pairs of breast cancer-unaffected and breast cancer-affected BRCA1 mutation carriers, each pair was from the same family carrying the same BRCA1 mutation. RESULTS We identified a group of 'beneficial' variants enriched in the breast cancer-unaffected carrier group. These were the common variants in human population distributed in multiple genes involved in multiple functionally important pathways. We found a single-nucleotide polymorphism, rs3735400 located in ANLN gene, which plays an essential role in controlling cytokinesis and is often found to be overexpressed in cancer. The carriers of this variant had lower cumulative risk of developing breast cancer; overexpression of the variant-containing ANLN decreased ANLN nuclear localization suppressed expression of the variant-containing ANLN, and decreased the cellular proliferation respectively. CONCLUSION Our findings support our hypothesis that common genetic variants can be evolutionarily selected in BRCA1 mutation carrier population to counterpart the oncogenic effects imposed by mutation predisposition in BRCA1, contributing to the incomplete penetrance.
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Affiliation(s)
- Bradley Downs
- Department of Genetics, Cell Biology and Anatomy, College of Medicine, USA
| | - Simon Sherman
- Eppley Institute for Research in Cancer and Allied Diseases, USA
| | - Jian Cui
- Department of Genetics, Cell Biology and Anatomy, College of Medicine, USA
| | - Yeong C Kim
- Department of Genetics, Cell Biology and Anatomy, College of Medicine, USA
| | - Carrie Snyder
- Hereditary Cancer Center, Department of Preventive Medicine, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Maria Christensen
- Hereditary Cancer Center, Department of Preventive Medicine, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Jiangtao Luo
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Henry Lynch
- Hereditary Cancer Center, Department of Preventive Medicine, Creighton University School of Medicine, Omaha, NE 68178, USA.
| | - San Ming Wang
- Department of Genetics, Cell Biology and Anatomy, College of Medicine, USA; Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, SAR, China.
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43
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Wöckel A, Lux MP, Janni W, Hartkopf AD, Nabieva N, Taran FA, Overkamp F, Hadji P, Tesch H, Ettl J, Lüftner D, Müller V, Welslau M, Belleville E, Brucker SY, Schütz F, Fasching PA, Fehm TN, Schneeweiss A, Kolberg HC. Update Breast Cancer 2018 (Part 3) - Genomics, Individualized Medicine and Immune Therapies - in the Middle of a New Era: Prevention and Treatment Strategies for Early Breast Cancer. Geburtshilfe Frauenheilkd 2018; 78:1110-1118. [PMID: 30498278 PMCID: PMC6255743 DOI: 10.1055/a-0715-2821] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 08/23/2018] [Indexed: 02/08/2023] Open
Abstract
In primary early breast cancer, the aim of treatment planning is to obtain an increasingly better understanding of the disease. The identification of patients with an excellent prognosis could help this group avoid unnecessary treatments. Furthermore, the planning of treatment is becoming increasingly patient-focussed. There is a growing understanding of those patients who benefit particularly from chemotherapy, as well as of those who could benefit from immunotherapy. Studies conducted on immunotherapies will be published shortly. Smaller individual studies offer an initial insight into the efficacy of checkpoint inhibitors (anti-PD1/PDL1 therapies). Not least, one of the largest breast cancer studies of all times has recently come to an end. The use of a multigene test has shown that it is sufficient to identify patients with such a good prognosis that chemotherapy is unnecessary. This review article is intended to summarise the current studies and give an outlook on current developments.
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Affiliation(s)
- Achim Wöckel
- Department of Gynecology and Obstetrics, University Hospital Würzburg, Germany
| | - Michael P Lux
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Andreas D Hartkopf
- Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
| | - Naiba Nabieva
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Florin-Andrei Taran
- Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
| | | | - Peyman Hadji
- Department of Bone Oncology, Nordwest Hospital, Frankfurt, Germany
| | - Hans Tesch
- Oncology Practice at Bethanien Hospital Frankfurt, Frankfurt, Germany
| | - Johannes Ettl
- Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Diana Lüftner
- Charité University Hospital, Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology and Tumour Immunology, Berlin, Germany
| | - Volkmar Müller
- Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany
| | - Manfred Welslau
- Onkologie Aschaffenburg, Hämatolo-Onkologische Schwerpunktpraxis am Klinikum Aschaffenburg, Aschaffenburg, Germany
| | | | - Sara Y Brucker
- Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
| | - Florian Schütz
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
| | - Peter A Fasching
- Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Tanja N Fehm
- Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Andreas Schneeweiss
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.,National Center for Tumor Diseases, Division Gynecologic Oncology, University Hospital Heidelberg, Heidelberg, Germany
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44
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Gao A, Sun T, Ma G, Cao J, Hu Q, Chen L, Wang Y, Wang Q, Sun J, Wu R, Wu Q, Zhou J, Liu L, Hu J, Dong JT, Zhu Z. LEM4 confers tamoxifen resistance to breast cancer cells by activating cyclin D-CDK4/6-Rb and ERα pathway. Nat Commun 2018; 9:4180. [PMID: 30301939 PMCID: PMC6177406 DOI: 10.1038/s41467-018-06309-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 07/02/2018] [Indexed: 02/07/2023] Open
Abstract
The elucidation of molecular events that confer tamoxifen resistance to estrogen receptor α (ER) positive breast cancer is of major scientific and therapeutic importance. Here, we report that LEM4 overexpression renders ER+ breast cancer cells resistant to tamoxifen by activating the cyclin D-CDK4/6 axis and the ERα signaling. We show that LEM4 overexpression accelerates tumor growth. Interaction with LEM4 stabilizes CDK4 and Rb, promotes Rb phosphorylation and the G1/S phase transition. LEM4 depletion or combined tamoxifen and PD0332991 treatment significantly reverses tamoxifen resistance. Furthermore, LEM4 interacts with and stabilizes both Aurora-A and ERα, promotes Aurora-A mediated phosphorylation of ERα-Ser167, leading to increase in ERα DNA-binding and transactivation activity. Elevated levels of LEM4 correlates with poorer relapse-free survival in patients with ER+ breast cancer undergoing endocrine therapy. Thus, LEM4 represents a prognostic marker and an attractive target for breast cancer therapeutics. Functional antagonism of LEM4 could overcome tamoxifen resistance.
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Affiliation(s)
- Ang Gao
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Tonghua Sun
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Gui Ma
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jiangran Cao
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Qingxia Hu
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Ling Chen
- Department of Pathology, Tianjin Central Hospital of Gynecology and Obstetrics, Tianjin, 300100, China
| | - Yanxin Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Qianying Wang
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jiafu Sun
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Rui Wu
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Qiao Wu
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jiaxi Zhou
- State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Lin Liu
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Junjie Hu
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Jin-Tang Dong
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
- Department of Hematology and Medical Oncology, School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia.
| | - Zhengmao Zhu
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
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45
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Vick EJ, Richardson N, Patel K, Delgado Ramos GM, Altahan A, Alloway T, Martin MG. Age-Related Chromosomal Aberrations in Patients with Diffuse Large B-Cell Lymphoma: An In Silico Approach. World J Oncol 2018; 9:97-103. [PMID: 30220946 PMCID: PMC6134989 DOI: 10.14740/wjon1136w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 08/27/2018] [Indexed: 02/05/2023] Open
Abstract
Background In diffuse large B-cell lymphoma (DLBCL), chromosomal aberrations are known to increase with advancing age. Our study aims to determine if there are other genetic aberrations associated with DLBCL based on age. Methods Using the Mitelman Database of Genetic Aberrations, we were able to find 749 cases of DLBCL with genomic aberrations with a median age of 62 years. Patients with DLBCL chromosomal aberration analysis results were divided into four groups based on age (0 - 30, 31 - 50, 51 - 70, > 71 years) and examined by chi-square analysis and Mantel-Cox for survival analysis. Results Ten aberrations were found to be significant with a particular age range: t(2;3), trisomy 19p13, trisomy 18q21, trisomy 3, trisomy 7, trisomy 14, trisomy 16, trisomy 18, monosomy 3 and monosomy 11, and survival ranged from 7 to 25 months. Conclusion This suggests that patients with DLBCL are likely to accumulate specific translocations depending on their age at the onset of DLBCL.
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Affiliation(s)
- Eric J. Vick
- Department of Internal Medicine, University of Cincinnati, Cincinnati OH, USA
| | - Noah Richardson
- College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Kruti Patel
- Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Glenda M. Delgado Ramos
- Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Alaa Altahan
- Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Taylor Alloway
- Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Michael G. Martin
- Department of Hematology and Oncology, The West Cancer Center, Memphis, TN, USA
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46
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Wunderle M, Olmes G, Nabieva N, Häberle L, Jud SM, Hein A, Rauh C, Hack CC, Erber R, Ekici AB, Hoyer J, Vasileiou G, Kraus C, Reis A, Hartmann A, Schulz-Wendtland R, Lux MP, Beckmann MW, Fasching PA. Risk, Prediction and Prevention of Hereditary Breast Cancer - Large-Scale Genomic Studies in Times of Big and Smart Data. Geburtshilfe Frauenheilkd 2018; 78:481-492. [PMID: 29880983 PMCID: PMC5986564 DOI: 10.1055/a-0603-4350] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 04/09/2018] [Accepted: 04/09/2018] [Indexed: 12/24/2022] Open
Abstract
Over the last two decades genetic testing for mutations in
BRCA1
and
BRCA2
has become standard of care for women and men who are at familial risk for breast or ovarian cancer. Currently, genetic testing more often also includes so-called panel genes, which are assumed to be moderate-risk genes for breast cancer. Recently, new large-scale studies provided more information about the risk estimation of those genes. The utilization of information on panel genes with regard to their association with the individual breast cancer risk might become part of future clinical practice. Furthermore, large efforts have been made to understand the influence of common genetic variants with a low impact on breast cancer risk. For this purpose, almost 450 000 individuals have been genotyped for almost 500 000 genetic variants in the OncoArray project. Based on first results it can be assumed that – together with previously identified common variants – more than 170 breast cancer risk single nucleotide polymorphisms can explain up to 18% of familial breast cancer risk. The knowledge about genetic and non-genetic risk factors and its implementation in clinical practice could especially be of use for individualized prevention. This includes an individualized risk prediction as well as the individualized selection of screening methods regarding imaging and possible lifestyle interventions. The aim of this review is to summarize the most recent developments in this area and to provide an overview on breast cancer risk genes, risk prediction models and their utilization for the individual patient.
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Affiliation(s)
- Marius Wunderle
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Gregor Olmes
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Naiba Nabieva
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Lothar Häberle
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.,Biostatistics Unit, Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Sebastian M Jud
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Alexander Hein
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Claudia Rauh
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Carolin C Hack
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Ramona Erber
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Arif B Ekici
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Juliane Hoyer
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Georgia Vasileiou
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Cornelia Kraus
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - André Reis
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Rüdiger Schulz-Wendtland
- Institute of Diagnostic Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Michael P Lux
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Matthias W Beckmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Peter A Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
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47
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Flister MJ, Bergom C. Genetic Modifiers of the Breast Tumor Microenvironment. Trends Cancer 2018; 4:429-444. [PMID: 29860987 DOI: 10.1016/j.trecan.2018.04.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 04/13/2018] [Accepted: 04/16/2018] [Indexed: 02/06/2023]
Abstract
Multiple nonmalignant cell types in the tumor microenvironment (TME) impact breast cancer risk, metastasis, and response to therapy, yet most heritable mechanisms that influence TME cell function and breast cancer outcomes are largely unknown. Breast cancer risk is ∼30% heritable and >170 genetic loci have been associated with breast cancer traits. However, the majority of candidate genes have poorly defined mechanistic roles in breast cancer biology. Research indicates that breast cancer risk modifiers directly impact cancer cells, yet it is equally plausible that some modifier alleles impact the nonmalignant TME. The objective of this review is to examine the list of current breast cancer candidate genes that may modify breast cancer risk and outcome through the TME.
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Affiliation(s)
- Michael J Flister
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
| | - Carmen Bergom
- Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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48
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A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies. Am J Hum Genet 2018; 102:890-903. [PMID: 29727689 DOI: 10.1016/j.ajhg.2018.03.016] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 03/13/2018] [Indexed: 11/22/2022] Open
Abstract
Genome-wide association studies (GWASs) have identified more than 150 common genetic loci for breast cancer risk. However, the target genes and underlying mechanisms remain largely unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using normal or tumor breast transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project. We identified a total of 101 genes for 51 lead variants after combing the results of a meta-analysis of METABRIC and TCGA, and the results from GTEx at a Benjamini-Hochberg (BH)-adjusted p < 0.05. Using luciferase reporter assays in both estrogen-receptor positive (ER+) and negative (ER-) cell lines, we showed that alternative alleles of potential functional single-nucleotide polymorphisms (SNPs), rs11552449 (DCLRE1B), rs7257932 (SSBP4), rs3747479 (MRPS30), rs2236007 (PAX9), and rs73134739 (ATG10), could significantly change promoter activities of their target genes compared to reference alleles. Furthermore, we performed in vitro assays in breast cancer cell lines, and our results indicated that DCLRE1B, MRPS30, and ATG10 played a vital role in breast tumorigenesis via certain disruption of cell behaviors. Our findings revealed potential target genes for associations of genetic susceptibility risk loci and provided underlying mechanisms for a better understanding of the pathogenesis of breast cancer.
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49
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Klepsch V, Hermann-Kleiter N, Do-Dinh P, Jakic B, Offermann A, Efremova M, Sopper S, Rieder D, Krogsdam A, Gamerith G, Perner S, Tzankov A, Trajanoski Z, Wolf D, Baier G. Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade. Nat Commun 2018; 9:1538. [PMID: 29670099 PMCID: PMC5906604 DOI: 10.1038/s41467-018-04004-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 03/28/2018] [Indexed: 12/16/2022] Open
Abstract
Analyzing mouse tumor models in vivo, human T cells ex vivo, and human lung cancer samples, we provide direct evidence that NR2F6 acts as an immune checkpoint. Genetic ablation of Nr2f6, particularly in combination with established cancer immune checkpoint blockade, efficiently delays tumor progression and improves survival in experimental mouse models. The target genes deregulated in intratumoral T lymphocytes upon genetic ablation of Nr2f6 alone or together with PD-L1 blockade reveal multiple advantageous transcriptional alterations. Acute Nr2f6 silencing in both mouse and human T cells induces hyper-responsiveness that establishes a non-redundant T-cell-inhibitory function of NR2F6. NR2F6 protein expression in T-cell-infiltrating human NSCLC is upregulated in 54% of the cases (n = 303) and significantly correlates with PD-1 and CTLA-4 expression. Our data define NR2F6 as an intracellular immune checkpoint that suppresses adaptive anti-cancer immune responses and set the stage for clinical validation of targeting NR2F6 for next-generation immuno-oncological regimens. Immune checkpoints blockade (ICB) is a viable anti-cancer strategy. Here the authors show that nuclear receptor NR2F6 acts as an immune checkpoint in T cells and, using mouse models and human T cells, they show NR2F6 inhibition might improve current ICB therapy or work as an alternative therapeutic strategy.
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Affiliation(s)
- Victoria Klepsch
- Division of Translational Cell Genetics, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Natascha Hermann-Kleiter
- Division of Translational Cell Genetics, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Patricia Do-Dinh
- Division of Translational Cell Genetics, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Bojana Jakic
- Division of Translational Cell Genetics, Medical University of Innsbruck, 6020, Innsbruck, Austria
| | - Anne Offermann
- Pathology of the University Hospital Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Lung Center, 23538, Leubeck, Germany
| | - Mirjana Efremova
- Biocenter, Division of Bioinformatics, Medical University of Innsbruck, 6030, Innsbruck, Austria
| | - Sieghart Sopper
- Tumor Immunology, Tyrolean Cancer Institute & Internal Medicine V, 6020, Innsbruck, Austria
| | - Dietmar Rieder
- Biocenter, Division of Bioinformatics, Medical University of Innsbruck, 6030, Innsbruck, Austria
| | - Anne Krogsdam
- Biocenter, Division of Bioinformatics, Medical University of Innsbruck, 6030, Innsbruck, Austria
| | - Gabriele Gamerith
- Tumor Immunology, Tyrolean Cancer Institute & Internal Medicine V, 6020, Innsbruck, Austria
| | - Sven Perner
- Pathology of the University Hospital Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Lung Center, 23538, Leubeck, Germany
| | - Alexandar Tzankov
- Department of Pathology, University of Basel, University Hospital Basel, 4031, Basel, Switzerland
| | - Zlatko Trajanoski
- Tumor Immunology, Tyrolean Cancer Institute & Internal Medicine V, 6020, Innsbruck, Austria
| | - Dominik Wolf
- Tumor Immunology, Tyrolean Cancer Institute & Internal Medicine V, 6020, Innsbruck, Austria.,Medical Clinic III, Oncology, Hematology & Rheumatology, University Clinic Bonn, 53127, Bonn, Germany
| | - Gottfried Baier
- Division of Translational Cell Genetics, Medical University of Innsbruck, 6020, Innsbruck, Austria.
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50
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Reiner AS, Sisti J, John EM, Lynch CF, Brooks JD, Mellemkjær L, Boice JD, Knight JA, Concannon P, Capanu M, Tischkowitz M, Robson M, Liang X, Woods M, Conti DV, Duggan D, Shore R, Stram DO, Thomas DC, Malone KE, Bernstein L, Bernstein JL. Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women's Environmental Cancer and Radiation Epidemiology Study. J Clin Oncol 2018; 36:1513-1520. [PMID: 29620998 DOI: 10.1200/jco.2017.77.3424] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose The Women's Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.
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Affiliation(s)
- Anne S Reiner
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Julia Sisti
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Esther M John
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Charles F Lynch
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Jennifer D Brooks
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Lene Mellemkjær
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - John D Boice
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Julia A Knight
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Patrick Concannon
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Marinela Capanu
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Marc Tischkowitz
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Mark Robson
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Xiaolin Liang
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Meghan Woods
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - David V Conti
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - David Duggan
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Roy Shore
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Daniel O Stram
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Duncan C Thomas
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Kathleen E Malone
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Leslie Bernstein
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | - Jonine L Bernstein
- Anne S. Reiner, Julia Sisti, Marinela Capanu, Mark Robson, Xiaolin Liang, Meghan Woods, and Jonine L. Bernstein, Memorial Sloan Kettering Cancer Center; Mark Robson, Cornell University; Roy Shore, New York University School of Medicine, New York, NY; Esther M. John, Cancer Prevention Institute of California, Fremont, and Stanford School of Medicine, Stanford; David V. Conti, Daniel O. Stram, and Duncan C. Thomas, University of Southern California, Los Angeles; Leslie Bernstein, City of Hope National Medical Center, Duarte, CA; Charles F. Lynch, University of Iowa, Iowa City, IA; Jennifer D. Brooks and Julia A. Knight, University of Toronto; Julia A. Knight, Sinai Health System, Toronto, Ontario, Canada; Lene Mellemkjær, Danish Cancer Society Research Center, Copenhagen, Denmark; John D. Boice, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, TN; Patrick Concannon, University of Florida, Gainesville, FL; Marc Tischkowitz, University of Cambridge, Cambridge, United Kingdom; David Duggan, Translational Genomics Research Institute, Phoenix, AZ; and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA
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