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Arranz-Ledo M, Infante M, Lastra E, Olaverri A, Orozco M, Mateo LC, Martínez N, Hernández L, Durán M. Genetic Features of Tumours Arising in the Context of Suspected Hereditary Cancer Syndromes with RAD50, RAD51C/D, and BRIP1 Germline Mutations, Results of NGS-Reanalysis of BRCA/MMR-Negative Families. Genes (Basel) 2025; 16:458. [PMID: 40282418 PMCID: PMC12026886 DOI: 10.3390/genes16040458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/10/2025] [Accepted: 04/13/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Despite the well-established role of the BRCA and mismatch repair (MMR) genes in DNA damage repair pathways, a substantial proportion of familial cancer cases still lack pathogenic variants in those genes. Next Generation Sequencing (NGS) panels have emerged as a powerful tool to identify hereditary cancer at-risk individuals and subsequently provide them with accurate management. MATERIALS AND METHODS Families harbouring PVs in RAD50, RAD51C, RAD51D, and BRIP1 were identified by analysing a cancer-predisposing genes panel using Ion S5 system technology. A retrospective cohort of 155 families tested only for the BRCAs of MMR genes were reanalysed, prompted by an increase in familial cases or new cancer diagnoses among index cases. RESULTS We identified 40 families through molecular reanalysis (33 with Hereditary Breast and Ovarian Cancer (HBOC) and 7 with Lynch Syndrome (LS)), with positive test results among 155 families lacking BRCA or MMR mutations. The most frequently mutated genes after ATM and CHEK2 were BRIP1, RAD51D, and RAD51C with 16, 13, and 9 positive families, respectively. The phenotype-genotype correlations not only revealed ovarian and HER-negative breast cancer predispositions but also other cancer types, particularly lung and gastric, and individuals with a second or third distinct cancer episode. CONCLUSIONS Broader ranges of malignancies, including gastric, lung, and bladder, have been identified among BRIP1, RAD51D, and RAD51C positive families. The results generated using NGS provide a comprehensive genetic landscape in each patient that could explain the diversity of phenotypes shown in PV families that, combined with non-genetic factors, might enable accurate surveillance and personalized treatments. NGS reanalysis doubled our diagnostic yield and was a good strategy to identify hereditary cancer families that would otherwise be overlooked.
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Affiliation(s)
- Mónica Arranz-Ledo
- Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), C/Sanz y Forés 3, 47003 Valladolid, Spain; (M.A.-L.); (N.M.); (L.H.); (M.D.)
| | - Mar Infante
- Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), C/Sanz y Forés 3, 47003 Valladolid, Spain; (M.A.-L.); (N.M.); (L.H.); (M.D.)
| | - Enrique Lastra
- Unit of Genetic Counseling in Cancer, Complejo Hospitalario de Burgos, 09006 Burgos, Spain;
| | - Amaya Olaverri
- Unit of Genetic Counseling in Cancer, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain; (A.O.); (M.O.); (L.C.M.)
| | - Marta Orozco
- Unit of Genetic Counseling in Cancer, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain; (A.O.); (M.O.); (L.C.M.)
| | - Lucia C. Mateo
- Unit of Genetic Counseling in Cancer, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain; (A.O.); (M.O.); (L.C.M.)
| | - Noemí Martínez
- Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), C/Sanz y Forés 3, 47003 Valladolid, Spain; (M.A.-L.); (N.M.); (L.H.); (M.D.)
| | - Lara Hernández
- Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), C/Sanz y Forés 3, 47003 Valladolid, Spain; (M.A.-L.); (N.M.); (L.H.); (M.D.)
| | - Mercedes Durán
- Cancer Genetics Group, Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid-Spanish National Research Council (UVa-CSIC), C/Sanz y Forés 3, 47003 Valladolid, Spain; (M.A.-L.); (N.M.); (L.H.); (M.D.)
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Kazik J. Prostate cancer genetic background. The introduction of genetic testing in the determination of high-risk prostate cancer cases and selection of targeted chemotherapy in advanced prostate cancer patients. Cent European J Urol 2024; 77:625-636. [PMID: 40313693 PMCID: PMC12042403 DOI: 10.5173/ceju.2024.0049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 09/02/2024] [Indexed: 05/03/2025] Open
Abstract
Introduction Prostate cancer (PCa) is a major challenge in urology, with increasing incidence and mortality. Despite advances in diagnosis and treatment, certain patient groups remain poorly served. Genetic factors, particularly in hereditary prostate cancer (HPCa), are now recognized as significant contributors to disease progression. This review focuses on the role of genetic mutations in PCa, their impact on diagnosis, and management. Material and methods This review summarizes current literature on genetic mutations linked to PCa, including BRCA1, BRCA2, ATM, CHEK2, and others. These mutations are associated with more aggressive disease, earlier onset, and may influence treatment strategies. Guidelines from the Philadelphia Prostate Cancer Consensus Conference (PPCCC), the American National Comprehensive Cancer Network (NCCN), and the European Association of Urology (EAU) on genetic testing are also discussed. Results Genetic screening is increasingly recommended for high-risk individuals, such as those with a family history or aggressive PCa. Identifying mutations allows for early detection and tailored treatment, including more frequent screening and targeted therapies. Specific mutations, like those in BRCA genes, can benefit from chemotherapy in advanced stages. Genetic testing provides valuable information to guide patient management, improving early detection and patient outcomes. Conclusions Genetic testing plays a crucial role in PCa management, enabling personalized care for high-risk patients. As genetic research advances, incorporating genetic screening into clinical practice will enhance early diagnosis and treatment outcomes, ultimately improving patient survival and quality of life.
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Affiliation(s)
- Jakub Kazik
- Department of Urology, Provincial Integrated Hospital in Elblag, Poland
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Kozłowski M, Borzyszkowska D, Golara A, Durys D, Piotrowska K, Kempińska-Podhorodecka A, Cymbaluk-Płoska A. Evaluation of BRIP-1 (FANCJ) and FANCI Protein Expression in Ovarian Cancer Tissue. Biomedicines 2024; 12:2652. [PMID: 39767562 PMCID: PMC11673538 DOI: 10.3390/biomedicines12122652] [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: 10/24/2024] [Revised: 11/15/2024] [Accepted: 11/19/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Ovarian cancer is one of the most common cancers in women. Markers associated with ovarian cancer are still being sought. The aim of this study was to evaluate the expression of BRIP-1 (FANCJ) and FANCI proteins in ovarian cancer tissue and to assess these expressions in differentiating the described clinical features. Methods: The study enrolled 68 patients with ovarian cancer. The cohort was divided into a HGSOC (high-grade serous ovarian cancer) group and a non-HGSOC group, which represented ovarian cancer other than HGSOC. Immunohistochemical evaluation of FANCI and BRIP-1 (FANCJ) protein expression in ovarian cancer tissue samples was performed. All statistical analyses were performed using StatView software (Carry, NC, USA). Results: The FANCI protein mostly showed moderate positive and strong positive expression, while BRIP-1 protein mostly showed no expression or positive expression. Patients with lower expression of FANCI and BRIP-1 showed differences in the clinical stage of HGSOC, which was not observed in patients with higher expression of these proteins. In addition, patients with lower BRIP-1 expression showed differences in menopausal status, which was not observed in patients with higher expression of this protein. Conclusions: This study shows that FANCI protein is a marker associated with lower FIGO stage and histologically high-grade cancer in a group of all ovarian cancers and in non-HGSOC.
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Affiliation(s)
- Mateusz Kozłowski
- Department of Reconstructive Surgery and Gynecological Oncology, Pomeranian Medical University in Szczecin, Al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland (A.G.)
| | - Dominika Borzyszkowska
- Department of Reconstructive Surgery and Gynecological Oncology, Pomeranian Medical University in Szczecin, Al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland (A.G.)
| | - Anna Golara
- Department of Reconstructive Surgery and Gynecological Oncology, Pomeranian Medical University in Szczecin, Al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland (A.G.)
| | - Damian Durys
- Department of Reconstructive Surgery and Gynecological Oncology, Pomeranian Medical University in Szczecin, Al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland (A.G.)
| | - Katarzyna Piotrowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | | | - Aneta Cymbaluk-Płoska
- Department of Reconstructive Surgery and Gynecological Oncology, Pomeranian Medical University in Szczecin, Al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland (A.G.)
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Foley GR, Marthick JR, Lucas SE, Raspin K, Banks A, Stanford JL, Ostrander EA, FitzGerald LM, Dickinson JL. Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants. Cancers (Basel) 2024; 16:2482. [PMID: 39001544 PMCID: PMC11240467 DOI: 10.3390/cancers16132482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/27/2024] [Accepted: 07/02/2024] [Indexed: 07/16/2024] Open
Abstract
Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10-4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.
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Affiliation(s)
- Georgea R Foley
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia
| | - James R Marthick
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia
| | - Sionne E Lucas
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia
| | - Kelsie Raspin
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia
| | - Annette Banks
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia
| | - Janet L Stanford
- Fred Hutchinson Cancer Center, 1100 Fairview Ave. N., M4-B874, Seattle, WA 98109, USA
| | - Elaine A Ostrander
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Liesel M FitzGerald
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia
| | - Joanne L Dickinson
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia
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Paulo P, Cardoso M, Brandão A, Pinto P, Falconi A, Pinheiro M, Cerveira N, Silva R, Santos C, Pinto C, Peixoto A, Maia S, Teixeira MR. Genetic landscape of homologous recombination repair genes in early-onset/familial prostate cancer patients. Genes Chromosomes Cancer 2023; 62:710-720. [PMID: 37436117 DOI: 10.1002/gcc.23190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/19/2023] [Accepted: 06/28/2023] [Indexed: 07/13/2023] Open
Abstract
Prostate cancer (PrCa) is one of the three most frequent and deadliest cancers worldwide. The discovery of PARP inhibitors for the treatment of tumors with deleterious variants in homologous recombination repair (HRR) genes has placed PrCa on the roadmap of precision medicine. However, the overall contribution of HRR genes to the 10%-20% of carcinomas arising in men with early-onset/familial PrCa has not been fully clarified. We used targeted next-generation sequencing (T-NGS) covering eight HRR genes (ATM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, and RAD51C) and an analysis pipeline querying both small and large genomic variations to clarify their global and relative contribution to hereditary PrCa predisposition in a series of 462 early-onset/familial PrCa cases. Deleterious variants were found in 3.9% of the patients, with CHEK2 and ATM being the most frequently mutated genes (38.9% and 22.2% of the carriers, respectively), followed by PALB2 and NBN (11.1% of the carriers, each), and finally by BRCA2, RAD51C, and BRIP1 (5.6% of the carriers, each). Using the same NGS data, exonic rearrangements were found in two patients, one pathogenic in BRCA2 and one of unknown significance in BRCA1. These results contribute to clarify the genetic heterogeneity that underlies PrCa predisposition in the early-onset and familial disease, respectively.
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Affiliation(s)
- Paula Paulo
- 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
| | - Marta Cardoso
- 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
| | - Andreia Brandão
- 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
| | - Pedro Pinto
- 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
| | - Ariane Falconi
- 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
| | - Manuela Pinheiro
- 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
| | - Nuno Cerveira
- 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 Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, Porto, Portugal
| | - Rui Silva
- 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
| | - Catarina Santos
- 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 Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, Porto, Portugal
| | - Carla Pinto
- 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 Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, Porto, Portugal
| | - Ana Peixoto
- 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 Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, Porto, Portugal
| | - Sofia Maia
- 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
- Medical Genetics Unit, Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Manuel R Teixeira
- 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 Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, Porto, Portugal
- School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
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Lukashchuk N, Barnicle A, Adelman CA, Armenia J, Kang J, Barrett JC, Harrington EA. Impact of DNA damage repair alterations on prostate cancer progression and metastasis. Front Oncol 2023; 13:1162644. [PMID: 37434977 PMCID: PMC10331135 DOI: 10.3389/fonc.2023.1162644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 06/01/2023] [Indexed: 07/13/2023] Open
Abstract
Prostate cancer is among the most common diseases worldwide. Despite recent progress with treatments, patients with advanced prostate cancer have poor outcomes and there is a high unmet need in this population. Understanding molecular determinants underlying prostate cancer and the aggressive phenotype of disease can help with design of better clinical trials and improve treatments for these patients. One of the pathways often altered in advanced prostate cancer is DNA damage response (DDR), including alterations in BRCA1/2 and other homologous recombination repair (HRR) genes. Alterations in the DDR pathway are particularly prevalent in metastatic prostate cancer. In this review, we summarise the prevalence of DDR alterations in primary and advanced prostate cancer and discuss the impact of alterations in the DDR pathway on aggressive disease phenotype, prognosis and the association of germline pathogenic alterations in DDR genes with risk of developing prostate cancer.
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Affiliation(s)
- Natalia Lukashchuk
- Translational Medicine, Oncology Research and Development (R&D), AstraZeneca, Cambridge, United Kingdom
| | - Alan Barnicle
- Translational Medicine, Oncology Research and Development (R&D), AstraZeneca, Cambridge, United Kingdom
| | - Carrie A. Adelman
- Translational Medicine, Oncology Research and Development (R&D), AstraZeneca, Cambridge, United Kingdom
| | - Joshua Armenia
- Oncology Data Science, Oncology Research and Development (R&D), AstraZeneca, Cambridge, United Kingdom
| | - Jinyu Kang
- Global Medicines Development, Oncology Research and Development (R&D), AstraZeneca, Gaithersburg, MD, United States
| | - J. Carl Barrett
- Translational Medicine, Oncology Research and Development (R&D), AstraZeneca, Waltham, MA, United States
| | - Elizabeth A. Harrington
- Translational Medicine, Oncology Research and Development (R&D), AstraZeneca, Cambridge, United Kingdom
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Long G, Hu K, Zhang X, Zhou L, Li J. Spectrum of BRCA1 interacting helicase 1 aberrations and potential prognostic and therapeutic implication: a pan cancer analysis. Sci Rep 2023; 13:4435. [PMID: 36932143 PMCID: PMC10023799 DOI: 10.1038/s41598-023-31109-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/06/2023] [Indexed: 03/19/2023] Open
Abstract
BRCA1 interacting helicase 1 (BRIP1) alteration was crucial in tumors and it was a potential therapeutic target in ovarian serous cystadenocarcinoma (OV). Although a small number of studies had focused on BRIP1, an extensive study of BRIP1 genetic mutation and its clinical application in different cancer types had not been analyzed. In the current study, we analyzed BRIP1 abnormal expression, methylation, mutation, and their clinical application via several extensive datasets, which covered over 10,000 tumor samples across more than 30 cancer types. The total mutation rate of BRIP1 was rare in pan cancer. Its alteration frequency, oncogenic effects, mutation, and therapeutic implications were different in each cancer. 242 BRIP1 mutations were found across 32 cancer types. UCEC had the highest alteration (mutation and CNV) frequency. In addition, BRIP1 was a crucial oncogenic factor in OV and BRCA. BRIP1 mutation in PRAD was targetable, and FDA had approved a new drug. Moreover, Kaplan-Meier curve analysis showed that BRIP1 expression and genetic aberrations were closely related to patient survival in several cancers, indicating their potential for application as new tumor markers and therapeutic targets. The current study profiled the total BRIP1 mutation spectrum and offered an extensive molecular outlook of BRIP1 in a pan cancer analysis. And it suggested a brand-new perspective for clinical cancer therapy.
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Affiliation(s)
- Guo Long
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Kuan Hu
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiaofang Zhang
- Departments of Burn and Plastic, Ningxiang People's Hospital, Hunan University of Chinese Medicine, Changsha, 410600, Hunan, China
| | - Ledu Zhou
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Juanni Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Wang R, Zhang J, Cui X, Wang S, Chen T, Niu Y, Du X, Kong J, Wang L, Jiang Y. Multimolecular characteristics and role of BRCA1 interacting protein C-terminal helicase 1 (BRIP1) in human tumors: a pan-cancer analysis. World J Surg Oncol 2023; 21:91. [PMID: 36907870 PMCID: PMC10010046 DOI: 10.1186/s12957-022-02877-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 12/09/2022] [Indexed: 03/13/2023] Open
Abstract
BACKGROUND The aberrant expression of BRIP1 was associated with several cancers; however, the panoramic picture of BRIP1 in human tumors remains unclear. This study aims to explore the pan-cancerous picture of the expression of BRIP1 across 33 human cancers. METHODS Based on the data from TCGA and GTEx, a series of bioinformatic analyses were applied to systematically explore the genetic landscape and biologic function of BRIP1 in 33 human tumors. RESULTS We observed prognosis-related differential BRIP1 expressions between various carcinomas and the corresponding normal tissues. "Basal transcription factors," "homologous recombination," "nucleotide excision repair," and DNA metabolism pathways may play a role in the functional mechanisms of BRIP1. Patients with uterine corpus endometrial carcinoma presented with the highest alteration frequency of BRIP1 (nearly 10%). Single-nucleotide and copy number variations of BRIP1 were noticed in multiple cancers, and the expression of BRIP1 is significantly regulated by copy number variation in breast invasive carcinoma and lung squamous cell carcinoma. BRIP1 expression is negatively correlated with the DNA methylation levels in many tumors and is associated with the activation of apoptosis, cell cycle, DNA damage response, and inhibition of hormone ER and RNS/MARK signaling pathways. Moreover, a positive correlation was observed between BRIP1 expression and the immune infiltration levels of cancer-associated fibroblasts and CD8+ T cells in lung adenocarcinoma. CONCLUSION Our pan-cancer analysis of BRIP1 provides a valuable resource for understanding the multimolecular characteristics and biological function of BRIP1 across human cancers.
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Affiliation(s)
- Ruohuang Wang
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, 266000, China
| | - Jisheng Zhang
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, 266000, China
| | - Xin Cui
- Qingdao Women and Children's Hospital, Qingdao University, Qingdao, Shandong, 266000, China
| | - Shun Wang
- The Ninth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200000, China
| | - Ting Chen
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, 266000, China
| | - Yanfang Niu
- Department of Clinical Laboratory, Yuncheng Central Hospital, Yuncheng, Shanxi, 044000, China
| | - Xiaoyun Du
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, 266000, China
| | - Jingwen Kong
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, 266000, China
| | - Lin Wang
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, 266000, China.
| | - Yan Jiang
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, 266000, China.
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Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer. Cancers (Basel) 2022; 14:cancers14153744. [PMID: 35954408 PMCID: PMC9367587 DOI: 10.3390/cancers14153744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 07/29/2022] [Indexed: 11/17/2022] Open
Abstract
Despite aggressive treatment and androgen-deprivation therapy, most prostate cancer patients ultimately develop castration-resistant prostate cancer (CRPC), which is associated with high mortality rates. However, the mechanisms governing the development of CRPC are poorly understood, and androgen receptor (AR) signaling has been shown to be important in CRPC through AR gene mutations, gene overexpression, co-regulatory factors, AR shear variants, and androgen resynthesis. A growing number of non-AR pathways have also been shown to influence the CRPC progression, including the Wnt and Hh pathways. Moreover, non-coding RNAs have been identified as important regulators of the CRPC pathogenesis. The present review provides an overview of the relevant literature pertaining to the mechanisms governing the molecular acquisition of castration resistance in prostate cancer, providing a foundation for future, targeted therapeutic efforts.
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Khan U, Khan MS. Prognostic Value Estimation of BRIP1 in Breast Cancer by Exploiting Transcriptomics Data Through Bioinformatics Approaches. Bioinform Biol Insights 2021; 15:11779322211055892. [PMID: 34840500 PMCID: PMC8619737 DOI: 10.1177/11779322211055892] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/09/2021] [Indexed: 01/04/2023] Open
Abstract
BRIP1 (Breast Cancer 1 Interacting Helicase 1) is a tumor suppressor gene that has vital function in preserving the genetic stability by repairing DNA damage though have significant associations with the onset of breast cancer (BC) if mutated or overexpressed. In this study, the prognostic value of BRIP1 gene was evaluated and validated through bioinformatics approaches utilizing transcriptomic (mRNA expression) data from several BC databases. To determine the prognostic value, the expression level of mRNA transcript was analyzed in context of comparison between breast tumor and normal tissues regarding clinical features, breast tumor subtypes, promoter methylation status, correlation level, mutation frequency, and survival of BC patients. BRIP1 expression was found to be significantly overexpressed in various BC molecular subtypes (e.g. PAM50, Sorlie’s) and clinical status (estrogen and progesterone receptor) than associated normal tissues which correlated with prognosis. Also, in promoter methylation level, its expression was observed as upregulated-hypomethylated regarding various clinicopathological features. Multiple data mining exhibited positive correlation between BRIP1 and INTS2 (Integrator Complex Subunit 2) expressions in BC. Further, mutation analysis revealed that BRIP1 gene was altered by acquiring both somatic and germline mutations. In addition, a total of 42 mutations; 24 missense, 8 fusion, 7 truncating, and 3 inframe mutations in BC patients was detected in BRIP1 protein. Moreover, higher BRIP1 expression was found to be correlated with poor disease-specific, disease metastasis-free, relapse-free, and overall survivals of BC patients. Since, overexpression of BRIP1 was identified to be associated with different clinical features, breast tumor subtypes, promoter methylation status, and survival of BC patients that may provide a risk of ensuing malignant transformation. Thus, lower expression of BRIP1 might hinder BC prognosis. We consider that this analysis will present a proof for BRIP1 gene to be a noteworthy molecular biomarker for BC prognosis.
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Affiliation(s)
- Umama Khan
- Biotechnology & Genetic Engineering Discipline, Khulna University, Khulna, Bangladesh
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11
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Hyatt C, McDougall C, Miller-Samuel S, Russo J. Genetic Counseling for Men with Prostate Cancer. Urol Clin North Am 2021; 48:323-337. [PMID: 34210488 DOI: 10.1016/j.ucl.2021.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Germline genetic testing is becoming more prevalent in urology clinics because of precision medicine for prostate cancer treatment. Genetic testing results can also influence cancer screening discussions for patients and/or their families. An important part of germline genetic testing is genetic counseling. This article provides an overview of the historical aspects of genetic counseling, discusses the components needed to provide proper genetic counseling, summarizes genes related to hereditary prostate cancer risk, and reviews genetic privacy and genetic discrimination concerns related to germline genetic testing.
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Affiliation(s)
- Colette Hyatt
- Familial Cancer Program, The University of Vermont Medical Center, Main Campus, East Pavilion, Level 2, 111 Colchester Avenue, Burlington, VT 05401, USA.
| | - Carey McDougall
- Sidney Kimmel Cancer Center, Clinical Cancer Genetics, 1100 Walnut Street, Suite 602, Philadelphia, PA 19107, USA
| | - Susan Miller-Samuel
- Sidney Kimmel Cancer Center, Clinical Cancer Genetics, 1100 Walnut Street, Suite 602, Philadelphia, PA 19107, USA
| | - Jessica Russo
- Sidney Kimmel Cancer Center, Clinical Cancer Genetics, 1100 Walnut Street, Suite 602, Philadelphia, PA 19107, USA
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12
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Abstract
Prostate cancer represents a significant health care burden in the United States due to its incidence, treatment-related morbidity, and cancer-specific mortality. The burden begins with prostate-specific antigen screening, which has been subject to controversy due to concerns of overdiagnosis and overtreatment. Advancements in molecular oncology have provided evidence for the inherited predisposition to prostate cancer, which could improve individualized, risk-adapted approaches to screening and mitigate the harms of routine screening. This review presents the current evidence for the genetic basis of prostate cancer and novel genetically informed, risk-adapted screening strategies for prostate cancer.
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13
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Vietri MT, D’Elia G, Caliendo G, Resse M, Casamassimi A, Passariello L, Albanese L, Cioffi M, Molinari AM. Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention. Int J Mol Sci 2021; 22:ijms22073753. [PMID: 33916521 PMCID: PMC8038462 DOI: 10.3390/ijms22073753] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/27/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared to age, race, ethnicity and environmental factors for PCa development. Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5–15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits. Here, we discuss the current knowledge of the genetic basis for inherited predisposition to PCa, the potential target therapy, and the role of active surveillance as a management strategy for patients with low-risk PCa. Finally, the current PCa guideline recommendations are reviewed.
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Affiliation(s)
- Maria Teresa Vietri
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (A.C.); (A.M.M.)
- U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naple, Italy; (G.D.); (G.C.); (M.R.); (L.P.); (L.A.); (M.C.)
- Correspondence: ; Tel.: +39-081-566-7639; Fax: +39-081-450-169
| | - Giovanna D’Elia
- U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naple, Italy; (G.D.); (G.C.); (M.R.); (L.P.); (L.A.); (M.C.)
| | - Gemma Caliendo
- U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naple, Italy; (G.D.); (G.C.); (M.R.); (L.P.); (L.A.); (M.C.)
| | - Marianna Resse
- U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naple, Italy; (G.D.); (G.C.); (M.R.); (L.P.); (L.A.); (M.C.)
| | - Amelia Casamassimi
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (A.C.); (A.M.M.)
| | - Luana Passariello
- U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naple, Italy; (G.D.); (G.C.); (M.R.); (L.P.); (L.A.); (M.C.)
| | - Luisa Albanese
- U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naple, Italy; (G.D.); (G.C.); (M.R.); (L.P.); (L.A.); (M.C.)
| | - Michele Cioffi
- U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naple, Italy; (G.D.); (G.C.); (M.R.); (L.P.); (L.A.); (M.C.)
| | - Anna Maria Molinari
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy; (A.C.); (A.M.M.)
- U.O.C. Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi Vanvitelli”, 80138 Naple, Italy; (G.D.); (G.C.); (M.R.); (L.P.); (L.A.); (M.C.)
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14
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[Familial prostate cancer and genetic predisposition]. Urologe A 2021; 60:567-575. [PMID: 33721089 DOI: 10.1007/s00120-021-01491-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Twenty percent of all prostate cancer patients have a positive family history (at least 1 first-degree relative with prostate cancer) and a part of these patients have a genetic predisposition. OBJECTIVES A literature search and analysis of studies investigating incidence, diagnosis, and clinical course of familial compared to sporadic prostate cancer as well as genetic predisposition was performed using PubMed and Embase. RESULTS Risk of prostate cancer depends on number, degree of relationship, and age of onset of affected men in the family. The incidence of familial prostate cancer is higher and the age of diagnosis lower compared to sporadic cases. The clinical course of the disease is comparable, but in individuals with a germline mutation, more intensive therapy is needed due to a more aggressive disease. CONCLUSIONS Crucial for risk assessment is a detailed family history, including creation of a pedigree with cancer family history if necessary. In high-risk families, genetic counselling and annual prostate-specific antigen (PSA) screening beginning at the age of 40 should be performed. Verification of a germline mutation requires more intensive therapy due to more aggressive disease.
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15
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Wokołorczyk D, Kluźniak W, Huzarski T, Gronwald J, Szymiczek A, Rusak B, Stempa K, Gliniewicz K, Kashyap A, Morawska S, Dębniak T, Jakubowska A, Szwiec M, Domagała P, Lubiński J, Narod SA, Akbari MR, Cybulski C. Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland. Int J Cancer 2020; 147:2793-2800. [PMID: 32875559 DOI: 10.1002/ijc.33272] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/14/2020] [Accepted: 08/19/2020] [Indexed: 01/04/2023]
Abstract
In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency of mutations in PCa susceptibility genes in Polish familial PCa cases and to estimate gene-related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer-free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High-grade (Gleason 8-10) tumors were seen in 56% of BRCA2, NBN or ATM carriers, compared to 21% of patients who tested negative for mutations in these genes (OR = 4.7, 95% CI 2.0-10.7, P = .0003). In summary, approximately 20% of familial prostate cancer cases in Poland can be attributed to mutations in eight susceptibility genes. Carriers of mutations in BRCA2, NBN and ATM develop aggressive disease and may benefit from intensified screening and/or chemotherapy.
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Affiliation(s)
- Dominika Wokołorczyk
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Wojciech Kluźniak
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Tomasz Huzarski
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.,Department of Clinical Genetics and Pathology, University of Zielona Góra, Poland
| | - Jacek Gronwald
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Agata Szymiczek
- Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada
| | - Bogna Rusak
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Klaudia Stempa
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Katarzyna Gliniewicz
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Aniruddh Kashyap
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Sylwia Morawska
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Tadeusz Dębniak
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Anna Jakubowska
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.,Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland
| | - Marek Szwiec
- Clinics of Oncology, University Hospital in Zielona Góra, Zielona Góra, Poland
| | - Paweł Domagała
- Department of Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Jan Lubiński
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Steven A Narod
- Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - Mohammad R Akbari
- Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - Cezary Cybulski
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
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16
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Brandão A, Paulo P, Teixeira MR. Hereditary Predisposition to Prostate Cancer: From Genetics to Clinical Implications. Int J Mol Sci 2020; 21:E5036. [PMID: 32708810 PMCID: PMC7404100 DOI: 10.3390/ijms21145036] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/10/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer (PrCa) ranks among the top five cancers for both incidence and mortality worldwide. A significant proportion of PrCa susceptibility has been attributed to inherited predisposition, with 10-20% of cases expected to occur in a hereditary/familial context. Advances in DNA sequencing technologies have uncovered several moderate- to high-penetrance PrCa susceptibility genes, most of which have previously been related to known hereditary cancer syndromes, namely the hereditary breast and ovarian cancer (BRCA1, BRCA2, ATM, CHEK2, and PALB2) and Lynch syndrome (MLH1, MSH2, MSH6, and PMS2) genes. Additional candidate genes have also been suggested, but further evidence is needed to include them in routine genetic testing. Recommendations based on clinical features, family history, and ethnicity have been established for more cost-efficient genetic testing of patients and families who may be at an increased risk of developing PrCa. The identification of alterations in PrCa predisposing genes may help to inform screening strategies, as well as treatment options, in the metastatic setting. This review provides an overview of the genetic basis underlying hereditary predisposition to PrCa, the current genetic screening recommendations, and the implications for clinical management of the disease.
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Affiliation(s)
- Andreia Brandão
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal; (A.B.); (P.P.)
| | - Paula Paulo
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal; (A.B.); (P.P.)
| | - Manuel R. Teixeira
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal; (A.B.); (P.P.)
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
- Biomedical Sciences Institute Abel Salazar (ICBAS), University of Porto, 4200-072 Porto, Portugal
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17
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Suszynska M, Ratajska M, Kozlowski P. BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases. J Ovarian Res 2020; 13:50. [PMID: 32359370 PMCID: PMC7196220 DOI: 10.1186/s13048-020-00654-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/24/2020] [Indexed: 12/24/2022] Open
Abstract
Background It is estimated that more than 20% of ovarian cancer cases are associated with a genetic predisposition that is only partially explained by germline mutations in the BRCA1 and BRCA2 genes. Recently, several pieces of evidence showed that mutations in three genes involved in the homologous recombination DNA repair pathway, i.e., BRIP1, RAD51C, and RAD51D, are associated with a high risk of ovarian cancer. To more precisely estimate the ovarian cancer risk attributed to BRIP1, RAD51C, and RAD51D mutations, we performed a meta-analysis based on a comparison of a total of ~ 29,400 ovarian cancer patients from 63 studies and a total of ~ 116,000 controls from the gnomAD database. Results The analysis allowed precise estimation of ovarian cancer risks attributed to mutations in BRIP1, RAD51C, and RAD51D, confirming that all three genes are ovarian cancer high-risk genes (odds ratio (OR) = 4.94, 95%CIs:4.07–6.00, p < 0.0001; OR = 5.59, 95%CIs:4.42–7.07, p < 0.0001; and OR = 6.94, 95%CIs:5.10–9.44, p < 0.0001, respectively). In the present report, we show, for the first time, a mutation-specific risk analysis associated with distinct, recurrent, mutations in the genes. Conclusions The meta-analysis provides evidence supporting the pathogenicity of BRIP1, RAD51C, and RAD51D mutations in relation to ovarian cancer. The level of ovarian cancer risk conferred by these mutations is relatively high, indicating that after BRCA1 and BRCA2, the BRIP1, RAD51C, and RAD51D genes are the most important ovarian cancer risk genes, cumulatively contributing to ~ 2% of ovarian cancer cases. The inclusion of the genes into routine diagnostic tests may influence both the prevention and the potential treatment of ovarian cancer.
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Affiliation(s)
- Malwina Suszynska
- Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Street, 61-704, Poznan, Poland
| | - Magdalena Ratajska
- Department of Pathology, Dunedin School of Medicine, University of Otago, 60 Hanover Street, Dunedin, 9016, New Zealand.,Department of Biology and Medical Genetics, Medical University of Gdansk, Debinki 1 St., 80-210, Gdansk, Poland
| | - Piotr Kozlowski
- Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Street, 61-704, Poznan, Poland.
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18
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Voutsadakis IA. Landscape of BRIP1 molecular lesions in gastrointestinal cancers from published genomic studies. World J Gastroenterol 2020; 26:1197-1207. [PMID: 32231423 PMCID: PMC7093310 DOI: 10.3748/wjg.v26.i11.1197] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 02/21/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND BRIP1 is a helicase that partners with BRCA1 in the homologous recombination (HR) step in the repair of DNA inter-strand cross-link lesions. It is a rare cause of hereditary ovarian cancer in patients with no mutations of BRCA1 or BRCA2. The role of the protein in other cancers such as gastrointestinal (GI) carcinomas is less well characterized but given its role in DNA repair it could be a candidate tumor suppressor similarly to the two BRCA proteins.
AIM To analyze the role of helicase BRIP1 (FANCJ) in GI cancers pathogenesis.
METHODS Publicly available data from genomic studies of esophageal, gastric, pancreatic, cholangiocarcinomas and colorectal cancers were interrogated to unveil the role of BRIP1 in these carcinomas and to discover associations of lesions in BRIP1 with other more common molecular defects in these cancers.
RESULTS Molecular lesions in BRIP1 were rare (3.6% of all samples) in GI cancers and consisted almost exclusively of mutations and amplifications. Among mutations, 40% were possibly pathogenic according to the OncoKB database. A majority of BRIP1 mutated GI cancers were hyper-mutated due to concomitant mutations in mismatch repair or polymerase ε and δ1 genes. No associations were discovered between amplifications of BRIP1 and any mutated genes. In gastroesophageal cancers BRIP1 amplification commonly co-occurs with ERBB2 amplification.
CONCLUSION Overall BRIP1 molecular defects do not seem to play a major role in GI cancers whereas mutations frequently occur in hypermutated carcinomas and co-occur with other HR genes mutations. Despite their rarity, BRIP1 defects may present an opportunity for therapeutic interventions similar to other HR defects.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, ON P6B 0A8, Canada
- Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON P0M 2Z0, Canada
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19
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Rantapero T, Wahlfors T, Kähler A, Hultman C, Lindberg J, Tammela TLJ, Nykter M, Schleutker J, Wiklund F. Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer. Genes (Basel) 2020; 11:genes11030314. [PMID: 32183364 PMCID: PMC7140841 DOI: 10.3390/genes11030314] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/13/2020] [Accepted: 03/13/2020] [Indexed: 12/30/2022] Open
Abstract
Germline variants in DNA repair genes are associated with aggressive prostate cancer (PrCa). The aim of this study was to characterize germline variants in DNA repair genes associated with lethal PrCa in Finnish and Swedish populations. Whole-exome sequencing was performed for 122 lethal and 60 unselected PrCa cases. Among the lethal cases, a total of 16 potentially damaging protein-truncating variants in DNA repair genes were identified in 15 men (12.3%). Mutations were found in six genes with CHEK2 (4.1%) and ATM (3.3%) being most frequently mutated. Overall, the carrier rate of truncating variants in DNA repair genes among men with lethal PrCa significantly exceeded the carrier rate of 0% in 60 unselected PrCa cases (p = 0.030), and the prevalence of 1.6% (p < 0.001) and 5.4% (p = 0.040) in Swedish and Finnish population controls from the Exome Aggregation Consortium. No significant difference in carrier rate of potentially damaging nonsynonymous single nucleotide variants between lethal and unselected PrCa cases was observed (p = 0.123). We confirm that DNA repair genes are strongly associated with lethal PrCa in Sweden and Finland and highlight the importance of population-specific assessment of variants contributing to PrCa aggressiveness.
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Affiliation(s)
- Tommi Rantapero
- Faculty of Medicine and Health Technology, Prostate Cancer Research Center, Tampere University, 33100 Tampere, Finland; (T.R.); (T.W.); (T.L.J.T.); (M.N.)
| | - Tiina Wahlfors
- Faculty of Medicine and Health Technology, Prostate Cancer Research Center, Tampere University, 33100 Tampere, Finland; (T.R.); (T.W.); (T.L.J.T.); (M.N.)
| | - Anna Kähler
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden; (A.K.); (C.H.); (J.L.)
| | - Christina Hultman
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden; (A.K.); (C.H.); (J.L.)
| | - Johan Lindberg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden; (A.K.); (C.H.); (J.L.)
| | - Teuvo L. J. Tammela
- Faculty of Medicine and Health Technology, Prostate Cancer Research Center, Tampere University, 33100 Tampere, Finland; (T.R.); (T.W.); (T.L.J.T.); (M.N.)
| | - Matti Nykter
- Faculty of Medicine and Health Technology, Prostate Cancer Research Center, Tampere University, 33100 Tampere, Finland; (T.R.); (T.W.); (T.L.J.T.); (M.N.)
| | - Johanna Schleutker
- Institute of Biomedicine, University of Turku, 20014 Turku, Finland;
- Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, 20521 Turku, Finland
| | - Fredrik Wiklund
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden; (A.K.); (C.H.); (J.L.)
- Correspondence: ; Tel.: +46-852483979
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20
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Taylor SJ, Arends MJ, Langdon SP. Inhibitors of the Fanconi anaemia pathway as potential antitumour agents for ovarian cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:26-52. [PMID: 36046263 PMCID: PMC9400734 DOI: 10.37349/etat.2020.00003] [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: 10/24/2019] [Accepted: 12/18/2019] [Indexed: 11/30/2022] Open
Abstract
The Fanconi anaemia (FA) pathway is an important mechanism for cellular DNA damage repair, which functions to remove toxic DNA interstrand crosslinks. This is particularly relevant in the context of ovarian and other cancers which rely extensively on interstrand cross-link generating platinum chemotherapy as standard of care treatment. These cancers often respond well to initial treatment, but reoccur with resistant disease and upregulation of DNA damage repair pathways. The FA pathway is therefore of great interest as a target for therapies that aim to improve the efficacy of platinum chemotherapies, and reverse tumour resistance to these. In this review, we discuss recent advances in understanding the mechanism of interstrand cross-link repair by the FA pathway, and the potential of the component parts as targets for therapeutic agents. We then focus on the current state of play of inhibitor development, covering both the characterisation of broad spectrum inhibitors and high throughput screening approaches to identify novel small molecule inhibitors. We also consider synthetic lethality between the FA pathway and other DNA damage repair pathways as a therapeutic approach.
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Affiliation(s)
- Sarah J Taylor
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - Mark J Arends
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - Simon P Langdon
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
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21
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Zhang W, van Gent DC, Incrocci L, van Weerden WM, Nonnekens J. Role of the DNA damage response in prostate cancer formation, progression and treatment. Prostate Cancer Prostatic Dis 2020; 23:24-37. [PMID: 31197228 PMCID: PMC8076026 DOI: 10.1038/s41391-019-0153-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/05/2019] [Accepted: 04/09/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Clinical and preclinical studies have revealed that alterations in DNA damage response (DDR) pathways may play an important role in prostate cancer (PCa) etiology and progression. These alterations can influence PCa responses to radiotherapy and anti-androgen treatment. The identification of DNA repair gene aberrations in PCa has driven the interest for further evaluation whether these genetic changes may serve as biomarkers for patient stratification. METHODS In this review, we summarize the current knowledge on DDR alterations in PCa, their potential impact on clinical interventions and prospects for improved management of PCa. We particularly focus on the influence of DDR gene mutations on PCa initiation and progression and describe the underlying mechanisms. RESULTS AND CONCLUSIONS A better understanding of these mechanisms, will contribute to better disease management as treatment strategies can be chosen based on the specific disease properties, since a growing number of treatments are targeting DDR pathway alterations (such as Poly(ADP-ribose) polymerase inhibitors). Furthermore, the recently discovered crosstalk between the DDR and androgen receptor signaling opens a new array of possible strategies to optimize treatment combinations. We discuss how these recent and ongoing studies will help to improve diagnostic, prognostic and therapeutic approaches for PCa management.
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Affiliation(s)
- Wenhao Zhang
- grid.5645.2000000040459992XDepartment of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands
| | - Dik C. van Gent
- grid.5645.2000000040459992XDepartment of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands ,grid.5645.2000000040459992XOncode Institute, Erasmus MC, Rotterdam, The Netherlands
| | - Luca Incrocci
- grid.508717.c0000 0004 0637 3764Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Wytske M. van Weerden
- grid.5645.2000000040459992XDepartment of Experimental Urology, Erasmus MC, Rotterdam, The Netherlands
| | - Julie Nonnekens
- grid.5645.2000000040459992XDepartment of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands ,grid.5645.2000000040459992XDepartment of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
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22
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Abstract
Prostatic adenocarcinoma (PCa) remains a significant health concern. Although localized PCa can be effectively treated, disseminated disease remains uniformly fatal. PCa is reliant on androgen receptor (AR); as such, first-line therapy for metastatic PCa entails suppression of AR signaling. Although initially effective, recurrent tumors reactivate AR function, leading to a lethal stage of disease termed castration-resistant PCa (CRPC). Recent findings implicate AR signaling in control of DNA repair and show that alterations in DNA damage repair pathways are strongly associated with disease progression and poor outcome. This review will address the DNA repair alterations observed in the clinical setting, explore the anticipated molecular and cellular consequence of DNA repair dysfunction, and consider clinical strategies for targeting tumors with altered DNA repair.
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Affiliation(s)
- Matthew J Schiewer
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania,19107.,The Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Karen E Knudsen
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania,19107.,Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.,Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.,Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.,The Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania 19107
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23
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Xu L, Chen J, Liu W, Liang C, Hu H, Huang J. Targeting androgen receptor-independent pathways in therapy-resistant prostate cancer. Asian J Urol 2019; 6:91-98. [PMID: 30775252 PMCID: PMC6363598 DOI: 10.1016/j.ajur.2018.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/23/2018] [Accepted: 10/29/2018] [Indexed: 12/13/2022] Open
Abstract
Since androgen receptor (AR) signaling is critically required for the development of prostate cancer (PCa), targeting AR axis has been the standard treatment of choice for advanced and metastatic PCa. Unfortunately, although the tumor initially responds to the therapy, treatment resistance eventually develops and the disease will progress. It is therefore imperative to identify the mechanisms of therapeutic resistance and novel molecular targets that are independent of AR signaling. Recent advances in pathology, molecular biology, genetics and genomics research have revealed novel AR-independent pathways that contribute to PCa carcinogenesis and progression. They include neuroendocrine differentiation, cell metabolism, DNA damage repair pathways and immune-mediated mechanisms. The development of novel agents targeting the non-AR mechanisms holds great promise to treat PCa that does not respond to AR-targeted therapies.
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Affiliation(s)
- Lingfan Xu
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
| | - Junyi Chen
- Department of Urology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Weipeng Liu
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chaozhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hailiang Hu
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
| | - Jiaoti Huang
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
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24
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Lee L, Ali S, Genega E, Reed D, Sokol E, Mathew P. Aggressive-Variant Microsatellite-Stable POLE Mutant Prostate Cancer With High Mutation Burden and Durable Response to Immune Checkpoint Inhibitor Therapy. JCO Precis Oncol 2018; 2:1-8. [DOI: 10.1200/po.17.00097] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Lisa Lee
- Lisa Lee, Elizabeth Genega, Dallas Reed, and Paul Mathew, Tufts Medical Center, Boston; Siraj Ali and Ethan Sokol, Foundation Medicine, Cambridge, MA
| | - Siraj Ali
- Lisa Lee, Elizabeth Genega, Dallas Reed, and Paul Mathew, Tufts Medical Center, Boston; Siraj Ali and Ethan Sokol, Foundation Medicine, Cambridge, MA
| | - Elizabeth Genega
- Lisa Lee, Elizabeth Genega, Dallas Reed, and Paul Mathew, Tufts Medical Center, Boston; Siraj Ali and Ethan Sokol, Foundation Medicine, Cambridge, MA
| | - Dallas Reed
- Lisa Lee, Elizabeth Genega, Dallas Reed, and Paul Mathew, Tufts Medical Center, Boston; Siraj Ali and Ethan Sokol, Foundation Medicine, Cambridge, MA
| | - Ethan Sokol
- Lisa Lee, Elizabeth Genega, Dallas Reed, and Paul Mathew, Tufts Medical Center, Boston; Siraj Ali and Ethan Sokol, Foundation Medicine, Cambridge, MA
| | - Paul Mathew
- Lisa Lee, Elizabeth Genega, Dallas Reed, and Paul Mathew, Tufts Medical Center, Boston; Siraj Ali and Ethan Sokol, Foundation Medicine, Cambridge, MA
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25
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Velázquez C, Esteban-Cardeñosa EM, Lastra E, Abella LE, de la Cruz V, Lobatón CD, Durán M, Infante M. Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer. Mol Carcinog 2018; 58:156-160. [PMID: 30230034 DOI: 10.1002/mc.22910] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 08/31/2018] [Accepted: 09/11/2018] [Indexed: 12/21/2022]
Abstract
BRIP1 is a component of the Fanconi Anemia/BRCA pathway responsible for DNA reparation via helicase activity. Some heterozygous variants in BRIP1 could contribute to Hereditary Breast Cancer through a defective DNA repair. The clinical utility of BRIP1 mutations in a familial cancer context is compromised by the conflicting interpretation of "variants of uncertain significance" (VUS). Defining the clinical significance of variants identified in genetic tests is a major challenge; therefore, studies that evaluate the biological effect of these variants are definitely necessary. To contribute to this purpose, we have characterized the variant c.550G>T of BRIP1, a missense mutation with little evidence about its pathogenicity. Since Human Splicing FinderTM predicts the creation of a new exonic splicing enhancer site we decided to perform cDNA analysis revealing that the c.550G>T mutation located in exon 6 led to an aberrant transcript causing exon 5 skipping. Our results demonstrate that the c.550G>T BRIP1 variant disrupts normal splicing, causing exon 5 skipping. Considering that the exon 5 encodes the helicase domain of BRIP1, it is expected an alteration of the function. This finding enhances the interpretation of this VUS, suggesting a potential pathogenic effect.
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Affiliation(s)
- Carolina Velázquez
- Cancer Genetics Group, Institute of Genetics and Molecular Biology (UVa-CSIC), Valladolid, Spain
| | - Eva M Esteban-Cardeñosa
- Cancer Genetics Group, Institute of Genetics and Molecular Biology (UVa-CSIC), Valladolid, Spain
| | - Enrique Lastra
- Unit of Genetic Counseling in Cancer, Complejo Hospitalario de Burgos, Burgos, Spain
| | - Luis E Abella
- Unit of Genetic Counseling in Cancer, Hospital Universitario Rio Hortega, Valladolid, Spain
| | - Virginia de la Cruz
- Unit of Genetic Counseling in Cancer, Hospital Universitario Rio Hortega, Valladolid, Spain
| | - Carmen D Lobatón
- Cancer Genetics Group, Institute of Genetics and Molecular Biology (UVa-CSIC), Valladolid, Spain
| | - Mercedes Durán
- Cancer Genetics Group, Institute of Genetics and Molecular Biology (UVa-CSIC), Valladolid, Spain
| | - Mar Infante
- Cancer Genetics Group, Institute of Genetics and Molecular Biology (UVa-CSIC), Valladolid, Spain
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26
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Zhen JT, Syed J, Nguyen KA, Leapman MS, Agarwal N, Brierley K, Llor X, Hofstatter E, Shuch B. Genetic testing for hereditary prostate cancer: Current status and limitations. Cancer 2018; 124:3105-3117. [PMID: 29669169 DOI: 10.1002/cncr.31316] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 12/06/2017] [Indexed: 12/22/2022]
Abstract
A significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Men who have multiple single-gene polymorphisms and a family history of prostate cancer have a significantly greater risk of developing prostate cancer. Numerous single-gene alterations have been confirmed to increase the risk of prostate cancer. These include breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively), mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and ataxia telangiectasia mutated (ATM). Currently, there are no uniform guidelines on the definition of hereditary prostate cancer and genetic testing. With the advent of next-generation sequencing, which is capable of testing multiple genes simultaneously, and the approval of olaparib for BRCA1/BRCA2 or ATM-mutated, metastatic, castrate-resistant prostate cancer, it is being recognized that the results of genetic testing have an impact on therapeutic strategies. In this review, the authors examine the role of genetic counseling and testing, the challenges of insurance coverage for testing, the available germline and somatic testing panels, and the complexity of each testing method and its implications. Cancer 2018. © 2018 American Cancer Society.
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Affiliation(s)
- Jun Tu Zhen
- Frank H. Netter School of Medicine at Quinnipiac University, North Haven, Connecticut.,Department of Urology, Yale School of Medicine, New Haven, Connecticut
| | - Jamil Syed
- Department of Urology, Yale School of Medicine, New Haven, Connecticut
| | - Kevin Anh Nguyen
- Department of Urology, Yale School of Medicine, New Haven, Connecticut
| | - Michael S Leapman
- Department of Urology, Yale School of Medicine, New Haven, Connecticut
| | - Neeraj Agarwal
- Huntsman Cancer Center, University of Utah School of Medicine, Salt Lake City, Utah
| | - Karina Brierley
- Cancer Genetics and Prevention Program, Smilow Cancer Center, Yale School of Medicine, New Haven, Connecticut
| | - Xavier Llor
- Cancer Genetics and Prevention Program, Smilow Cancer Center, Yale School of Medicine, New Haven, Connecticut
| | - Erin Hofstatter
- Cancer Genetics and Prevention Program, Smilow Cancer Center, Yale School of Medicine, New Haven, Connecticut
| | - Brian Shuch
- Department of Urology, Yale School of Medicine, New Haven, Connecticut.,Cancer Genetics and Prevention Program, Smilow Cancer Center, Yale School of Medicine, New Haven, Connecticut
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27
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Paulo P, Maia S, Pinto C, Pinto P, Monteiro A, Peixoto A, Teixeira MR. Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer. PLoS Genet 2018; 14:e1007355. [PMID: 29659569 PMCID: PMC5919682 DOI: 10.1371/journal.pgen.1007355] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 04/26/2018] [Accepted: 04/05/2018] [Indexed: 12/23/2022] Open
Abstract
Considering that mutations in known prostate cancer (PrCa) predisposition genes, including those responsible for hereditary breast/ovarian cancer and Lynch syndromes, explain less than 5% of early-onset/familial PrCa, we have sequenced 94 genes associated with cancer predisposition using next generation sequencing (NGS) in a series of 121 PrCa patients. We found monoallelic truncating/functionally deleterious mutations in seven genes, including ATM and CHEK2, which have previously been associated with PrCa predisposition, and five new candidate PrCa associated genes involved in cancer predisposing recessive disorders, namely RAD51C, FANCD2, FANCI, CEP57 and RECQL4. Furthermore, using in silico pathogenicity prediction of missense variants among 18 genes associated with breast/ovarian cancer and/or Lynch syndrome, followed by KASP genotyping in 710 healthy controls, we identified "likely pathogenic" missense variants in ATM, BRIP1, CHEK2 and TP53. In conclusion, this study has identified putative PrCa predisposing germline mutations in 14.9% of early-onset/familial PrCa patients. Further data will be necessary to confirm the genetic heterogeneity of inherited PrCa predisposition hinted in this study.
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Affiliation(s)
- Paula Paulo
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Sofia Maia
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Carla Pinto
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Pedro Pinto
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Augusta Monteiro
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Ana Peixoto
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Manuel R. Teixeira
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
- Biomedical Sciences Institute Abel Salazar (ICBAS), University of Porto, Porto, Portugal
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28
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Liu D, Zheng Y, Wang M, Deng Y, Lin S, Zhou L, Yang P, Dai C, Xu P, Hao Q, Song D, Kang H, Dai Z. Four common polymorphisms of BRIP1 (rs2048718, rs4988344, rs4986764, and rs6504074) and cancer risk: evidence from 13,716 cancer patients and 15,590 cancer-free controls. Aging (Albany NY) 2018; 10:266-277. [PMID: 29466248 PMCID: PMC5842853 DOI: 10.18632/aging.101388] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 02/09/2018] [Indexed: 11/25/2022]
Abstract
Previous studies have showed the associations between various BRCA1-interacting protein 1 (BRIP1) polymorphisms and cancer risk. But, these results were inconsistent. This meta-analysis based on 18 studies involving 13,716 cancer patients and 15,590 cancer-free controls is aimed at to evaluate the relationship between the four common SNPs of BRIP1 (rs2048718, rs4988344, rs4986764, and rs6504074) and cancer risk. The results showed a decreased risk of rs2048718 or rs4986764 for cervical cancer rather than breast cancer in the overall population (P < 0.05). However, rs6504074 was associated with gynecologic cancer risk among overall population (P < 0.05). Further stratification analyses by ethnicity indicated that all 4 polymorphisms (rs2048718, rs4988344, rs4986764, and rs6504074) were strongly related to cancer susceptibility in Chinese people (P < 0.05). This meta-analysis showed that rs6504074 may play a decreased risk of gynecologic cancer in the overall population. Rs4988344, rs4986764, and rs6504074 were significantly related to decreasing cancer risk in Chinese population.
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Affiliation(s)
- Di Liu
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
- Equal contribution
| | - Yi Zheng
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
- Equal contribution
| | - Meng Wang
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
- Equal contribution
| | - Yujiao Deng
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
| | - Shuai Lin
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
| | - Linghui Zhou
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
| | - Pengtao Yang
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
| | - Cong Dai
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
| | - Peng Xu
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
| | - Qian Hao
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
| | - Dingli Song
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
| | - Huafeng Kang
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
| | - Zhijun Dai
- Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an710004, China
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29
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Netto GJ, Eich ML, Varambally S. Prostate Cancer: An Update on Molecular Pathology with Clinical Implications. EUR UROL SUPPL 2017. [DOI: 10.1016/j.eursup.2017.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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30
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31
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Saunders EJ, Dadaev T, Leongamornlert DA, Olama AAA, Benlloch S, Giles GG, Wiklund F, Grönberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Neal D, Pasayan N, Khaw KT, Stanford JL, Blot WJ, Thibodeau SN, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Park JY, Kaneva R, Batra J, Teixeira MR, Pandha H, Govindasami K, Muir K, Easton DF, Eeles RA, Kote-Jarai Z. Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array. Br J Cancer 2016; 114:945-52. [PMID: 26964030 PMCID: PMC5379914 DOI: 10.1038/bjc.2016.50] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 02/05/2016] [Accepted: 02/09/2016] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.
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Affiliation(s)
- Edward J Saunders
- The Institute of Cancer Research
& Royal Marsden NHS Foundation Trust, 123 Old Brompton
Rd, London
SW7 3RP, UK
| | - Tokhir Dadaev
- The Institute of Cancer Research
& Royal Marsden NHS Foundation Trust, 123 Old Brompton
Rd, London
SW7 3RP, UK
| | - Daniel A Leongamornlert
- The Institute of Cancer Research
& Royal Marsden NHS Foundation Trust, 123 Old Brompton
Rd, London
SW7 3RP, UK
| | - Ali Amin Al Olama
- Centre for Cancer Genetic
Epidemiology, Department of Public Health and Primary Care, University of
Cambridge, Strangeways Laboratory, Worts Causeway,
Cambridge
CB1 8RN, UK
| | - Sara Benlloch
- Centre for Cancer Genetic
Epidemiology, Department of Public Health and Primary Care, University of
Cambridge, Strangeways Laboratory, Worts Causeway,
Cambridge
CB1 8RN, UK
| | - Graham G Giles
- Cancer Epidemiology Centre, The
Cancer Council Victoria, 1 Rathdowne Street,
Carlton Victoria, Australia
- Centre for Molecular, Environmental,
Genetic and Analytic Epidemiology, The University of Melbourne
3053, Victoria, Australia
| | - Fredrik Wiklund
- Department of Medical Epidemiology
and Biostatistics, Karolinska Institute, Stockholm
17177, Sweden
| | - Henrik Grönberg
- Department of Medical Epidemiology
and Biostatistics, Karolinska Institute, Stockholm
17177, Sweden
| | - Christopher A Haiman
- Department of Preventive Medicine,
Keck School of Medicine, University of Southern California & Norris
Comprehensive Cancer Center, Los Angeles,
CA
90089, USA
| | - Johanna Schleutker
- Department of Medical Biochemistry
and Genetics, University of Turku, Turku,
Finland
- Institute of Biomedical Technology
and BioMediTech, University of Tampere and FimLab Laboratories,
Tampere
33520, Finland
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry,
Herlev and Gentofte Hospital, Copenhagen University Hospital,
Herlev Ringvej 75
DK-2730, Herlev, Denmark
| | - Ruth C Travis
- Cancer Epidemiology Unit, Nuffield
Department of Population Health, University of Oxford,
Oxford
OX3 7LF, UK
| | - David Neal
- Surgical Oncology (Uro-Oncology:
S4), University of Cambridge, Addenbrooke's Hospital, Hills Road,
Cambridge & Cancer Research UK Cambridge Research Institute, Li Ka
Shing Centre, Cambridge
CB2 2QQ, UK
| | - Nora Pasayan
- University College London,
Department of Applied Health Research, 1-19 Torrington
Place, London
WC1E 7HB, UK
| | - Kay-Tee Khaw
- Cambridge Institute of Public
Health, University of Cambridge, Forvie Site, Robinson
Way, Cambridge
CB2 0SR, UK
| | - Janet L Stanford
- Department of Epidemiology, School
of Public Health, University of Washington & Division of Public
Health Sciences, Fred Hutchinson Cancer Research Center,
Seattle, WA, USA
| | - William J Blot
- International Epidemiology
Institute, 1455 Research Blvd., Suite 550,
Rockville
MD 20850, USA
| | | | - Christiane Maier
- Institute of Human Genetics,
University Hospital Ulm, Ulm
89075, Germany
| | - Adam S Kibel
- Division of Urologic Surgery,
Brigham and Women's Hospital, Dana-Farber Cancer Institute,
45 Francis Street- ASB II-3
Boston, MA, 02245,
USA
| | - Cezary Cybulski
- International Hereditary Cancer
Center, Department of Genetics and Pathology, Pomeranian Medical
University, Szczecin
70-115, Poland
| | - Lisa Cannon-Albright
- Division of Genetic Epidemiology,
Department of Medicine, University of Utah School of Medicine &
George E. Wahlen Department of Veterans Affairs Medical Center,
Salt Lake City, UT
84132, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology
and Aging Research, German Cancer Research Center (DKFZ), Heidelberg
& Division of Preventive Oncology, German Cancer Research Center
(DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg &
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ),
Heidelberg, Germany
| | - Jong Y Park
- Department of Cancer Epidemiology,
H. Lee Moffitt Cancer Center, 12902 Magnolia Drive,
Tampa, FL
33612, USA
| | - Radka Kaneva
- Molecular Medicine Center and
Department of Medical Chemistry and Biochemistry, Medical University -
Sofia, 2 Zdrave Street, Sofia
1431, Bulgaria
| | - Jyotsna Batra
- Australian Prostate Cancer Research
Centre-Qld, Institute of Health and Biomedical Innovation & School
of Biomedical Science, Queensland University of Technology,
Brisbane
4102, Australia
| | - Manuel R Teixeira
- Biomedical Sciences Institute
(ICBAS), Porto University, Porto, Portugal
- Department of Genetics, Portuguese
Oncology Institute, Porto, Portugal
4200-072, Portugal
| | - Hardev Pandha
- The University of Surrey,
Guildford, Surrey
GU2 7XH, UK
| | - Koveela Govindasami
- The Institute of Cancer Research
& Royal Marsden NHS Foundation Trust, 123 Old Brompton
Rd, London
SW7 3RP, UK
| | - Ken Muir
- Warwick Medical School, University
of Warwick, Coventry
CV4 7AL, UK
| | - Douglas F Easton
- Centre for Cancer Genetic
Epidemiology, Department of Public Health and Primary Care, University of
Cambridge, Strangeways Laboratory, Worts Causeway,
Cambridge
CB1 8RN, UK
| | - Rosalind A Eeles
- The Institute of Cancer Research
& Royal Marsden NHS Foundation Trust, 123 Old Brompton
Rd, London
SW7 3RP, UK
| | - Zsofia Kote-Jarai
- The Institute of Cancer Research
& Royal Marsden NHS Foundation Trust, 123 Old Brompton
Rd, London
SW7 3RP, UK
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Liu Y, Li H, Zhang R, Dang H, Sun P, Zou L, Zhang Y, Gao Y, Hu Y. Overexpression of the BRIP1 ameliorates chemosensitivity to cisplatin by inhibiting Rac1 GTPase activity in cervical carcinoma HeLa cells. Gene 2016; 578:85-91. [DOI: 10.1016/j.gene.2015.12.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 10/29/2015] [Accepted: 12/07/2015] [Indexed: 01/17/2023]
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Abstract
Much progress has been made in research for prostate cancer in the past decade. There is now greater understanding for the genetic basis of familial prostate cancer with identification of rare but high-risk mutations (eg, BRCA2, HOXB13) and low-risk but common alleles (77 identified so far by genome-wide association studies) that could lead to targeted screening of patients at risk. This is especially important because screening for prostate cancer based on prostate-specific antigen remains controversial due to the high rate of overdiagnosis and unnecessary prostate biopsies, despite evidence that it reduces mortality. Classification of prostate cancer into distinct molecular subtypes, including mutually exclusive ETS-gene-fusion-positive and SPINK1-overexpressing, CHD1-loss cancers, could allow stratification of patients for different management strategies. Presently, men with localised disease can have very different prognoses and treatment options, ranging from observation alone through to radical surgery, with few good-quality randomised trials to inform on the best approach for an individual patient. The survival of patients with metastatic prostate cancer progressing on androgen-deprivation therapy (castration-resistant prostate cancer) has improved substantially. In addition to docetaxel, which has been used for more than a decade, in the past 4 years five new drugs have shown efficacy with improvements in overall survival leading to licensing for the treatment of metastatic castration-resistant prostate cancer. Because of this rapid change in the therapeutic landscape, no robust data exist to inform on the selection of patients for a specific treatment for castration-resistant prostate cancer or the best sequence of administration. Moreover, the high cost of the newer drugs limits their widespread use in several countries. Data from continuing clinical and translational research are urgently needed to improve, and, crucially, to personalise management.
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Affiliation(s)
- Gerhardt Attard
- Division of Clinical Studies, The Institute of Cancer Research, London, UK; Prostate Cancer Targeted Therapy Group, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| | - Chris Parker
- Academic Urology Unit, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| | - Ros A Eeles
- Clinical Academic Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK; Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Fritz Schröder
- Erasmus University Medical Center, Rotterdam, Netherlands
| | - Scott A Tomlins
- Departments of Pathology Urology, Comprehensive Cancer Center and Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ian Tannock
- Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada
| | - Charles G Drake
- Division of Medical Oncology, Johns Hopkins Hospital, Baltimore, MA, USA
| | - Johann S de Bono
- Division of Clinical Studies, The Institute of Cancer Research, London, UK; Prostate Cancer Targeted Therapy Group, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK.
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A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck. Tumour Biol 2015; 37:8057-66. [PMID: 26711789 DOI: 10.1007/s13277-015-4682-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 12/16/2015] [Indexed: 01/21/2023] Open
Abstract
DNA double-strand breaks (DSBs) are one of the most serious forms of DNA damage to the cell, causing genomic instability and ultimately carcinogenesis. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) at the micro RNA (miRNA)-binding sites of DSB repair genes may influence cancer risk by dysregulating target gene expression. To test our hypothesis, we firstly performed functional prediction for common SNPs in DSB genes and found 12 potentially functional SNPs located at the miRNA-binding sites. We then investigated their associations with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. As a result, SNP rs7213430 in BRIP1 was found to be significantly associated with cancer risk (P trend = 0.021). Compared with the AA homozygotes, the G allele carriers had an increased risk of SCCHN (adjusted OR 1.16, 95 % CI 1.02-1.31). Marginal significance was found for another SNP rs15869 in BRCA2 (P = 0.053). Further, functional analyses showed that SNP rs7213430 is within the miR-101 seed-binding region, and the variant G allele could lead to significantly lower luciferase activity and BRIP1 mRNA expression, compared to the A allele with the presence of miR-101. Our results suggested that SNP rs7213430 in the 3'-UTR of BRIP1 might contribute to SCCHN susceptibility by affecting the binding activity of miR-101 and resulting in a decreased BRIP1 expression. Additional larger population and functional studies are warranted to confirm our findings.
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Zou W, Ma X, Hua W, Chen B, Huang Y, Wang D, Cai G. BRIP1 inhibits the tumorigenic properties of cervical cancer by regulating RhoA GTPase activity. Oncol Lett 2015; 11:551-558. [PMID: 26870246 PMCID: PMC4727061 DOI: 10.3892/ol.2015.3963] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 10/28/2015] [Indexed: 02/06/2023] Open
Abstract
Breast cancer 1, early onset (BRCA1)-interacting protein 1 (BRIP1), a DNA-dependent adenosine triphosphatase and DNA helicase, is required for BRCA-associated DNA damage repair functions, and may be associated with the tumorigenesis and aggressiveness of various cancers. The present study investigated the expression of BRIP1 in normal cervix tissues and cervical carcinoma via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry assays. BRIP1 expression was observed to be reduced in squamous cancer tissue and adenocarcinoma compared with normal cervix tissue, and there were significant correlations between the reduction in BRIP1 expression and unfavorable variables, including the International Federation of Gynecologists and Obstetricians stage and presence of lymph node metastases. In order to elucidate the role of BRIP1 in cervical cancer, a BRIP1 recombinant plasmid was constructed and overexpressed in a cervical cancer cell line (HeLa). The ectopic expression of BRIP1 markedly inhibited the tumorigenic properties of HeLa cells in vitro, as demonstrated by decreased cell growth, invasion and adhesion, and increased cell apoptosis. In addition, it was identified that the inhibitory tumorigenic properties of BRIP1 may be partly attributed to the attenuation of RhoA GTPase activity. The present study provides a novel insight into the essential role of BRIP1 in cervical cancer, and suggests that BRIP1 may be a useful therapeutic target for the treatment of this common malignancy.
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Affiliation(s)
- Wei Zou
- Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Xiangdong Ma
- Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Wei Hua
- Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Biliang Chen
- Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yanhong Huang
- Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Detang Wang
- Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Guoqing Cai
- Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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Hunter SM, Rowley SM, Clouston D, Li J, Lupat R, Krishnananthan N, Risbridger G, Taylor R, Bolton D, Campbell IG, Thorne H. Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer. Urol Oncol 2015; 34:120.e9-16. [PMID: 26585945 DOI: 10.1016/j.urolonc.2015.10.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 10/13/2015] [Accepted: 10/13/2015] [Indexed: 01/07/2023]
Abstract
OBJECTIVE A family history of prostate cancer (PC) is a well-recognized high-risk factor for the development of clinically significant PC. To date, traditional linkage and association studies have identified only a limited number of genes and specific gene variants that account for only a small proportion of PC risk. To identify novel PC predisposition genes we performed whole-exome sequencing of PC-affected men from families with a significant history of PC. METHODS AND MATERIALS Exome sequencing was performed on 5 PC-affected men from 3 families where there were multiple cases of PCs and where diagnostic testing returned a negative result for BRCA1 and BRCA2 mutations. Genotyping was performed for all potentially predisposing variants detected within each family on the affected and unaffected male participants. RESULTS Essential splice site, missense, and stop-lost variants were filtered against a recently published candidate gene list. A total of 19 truncating variants and 17 missense variants were identified for genotyping in all prostate-affected and unaffected male participants. In all, 3 missense variants, PCTP, MCRS1, and ATRIP, demonstrated complete segregation and 1 missense variant, PARP2, demonstrated partial segregation with PC. In addition, 3 truncating variants, CYP3A43, DOK3, and PLEKHH3, demonstrated complete segregation and 3 truncation mutations, HEATR5B, GPR124, and HKR1, demonstrated partial segregation with PC. No segregating variants between the 3 families were shared. CONCLUSIONS In all, 10 truncating or missense variants showed either complete or partial segregation with PC in the relevant families. CYP3A43 and PARP2 variants have been shown to occur in other familial PCs and our findings add to the contribution that these variants potentially have in the risk and development of PC in BRCAX cases.
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Affiliation(s)
- Sally M Hunter
- Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Australia
| | - Simone M Rowley
- Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Australia
| | | | - Jason Li
- Bioinformatics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - Richard Lupat
- Bioinformatics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
| | - Nishanth Krishnananthan
- kConFab Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Department of Urology, Austin Hospital, University of Melbourne, Heidelberg, Australia
| | - Gail Risbridger
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
| | - Renea Taylor
- Department of Physiology, Monash University, Clayton, Australia
| | - Damien Bolton
- Department of Urology, Austin Hospital, University of Melbourne, Heidelberg, Australia
| | - Ian G Campbell
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
| | - Heather Thorne
- kConFab Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
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Abstract
A wide array of molecular markers and genomic signatures, reviewed in this article, may soon be used as adjuncts to currently established screening strategies, prognostic parameters, and early detection markers. Markers of genetic susceptibility to PCA, recurrent epigenetic and genetic alterations, including ETS gene fusions, PTEN alterations, and urine-based early detection marker PCA3, are discussed. Impact of recent genome-wide assessment on our understanding of key pathways of PCA development and progression and their potential clinical implications are highlighted.
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Loss of heterozygosity for chromosomal regions 15q14-21.1, 17q21.31, and 13q12.3-13.1 and its relevance for prostate cancer. Med Oncol 2015; 32:246. [PMID: 26433958 PMCID: PMC4592700 DOI: 10.1007/s12032-015-0691-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 09/24/2015] [Indexed: 01/07/2023]
Abstract
Although prostate cancer is one of the most common cancers in men, the genetic defects underlying its pathogenesis remain poorly understood. DNA damage repair mechanisms have been implicated in human cancer. Accumulating evidence indicates that the fidelity of the response to DNA double-strand breaks is critical for maintaining genome integrity. RAD51 is a central player in double-strand break repair via homologous recombination, and its alterations may confer and increase the risk of cancer. RAD51 functioning depends on the indirect or direct interactions with BRCA1 and BRCA2. To evaluate the contribution of RAD51 to sporadic prostate cancer, loss of heterozygosity (LOH) for chromosomal region 15q14-21.1 (RAD51locus) was determined and compared to LOH in 17q21.31 (BRCA1 locus) and 13q12.3-13.1 (BRCA2 region). DNA was isolated from prostate biopsies and matched peripheral blood of 50 patients. The regions 15q14-21.1, 17q21.31, and 13q12.3-13.1 were examined using microsatellite markers on chromosome 15 (D15S118, D15S214, D15S1006), chromosome 17 (D17S855, D17S1323), and chromosome 13 (D13S260, D13S290), respectively. The LOH in tumors was analyzed by PCR with fluorescently labeled primers and an ABI PRISM 377 DNA Sequencer. Allele sizing was determined by GeneScan version 3.1.2 and Genotyper version 2.5 software (Applied Biosystems, USA). LOH was identified in 57.5, 23, and 40 % for chromosomal regions 15q14-21.1, 17q21.31, and 13q12.3-13.1, respectively. Twenty-six percent of studied cases manifested LOH for at least one marker in 15q14-21.1 exclusively. A significant correlation was found between LOH for studied region and PSAD (prostate-specific antigen density). The findings suggest that RAD51 may be considered as a prostate cancer susceptibility gene.
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Genetic Counseling for Fanconi Anemia: Crosslinking Disciplines. J Genet Couns 2014; 23:910-21. [DOI: 10.1007/s10897-014-9754-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 07/31/2014] [Indexed: 12/22/2022]
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Mostowska A, Hozyasz KK, Wójcicki P, Galas-Filipowicz D, Lasota A, Dunin-Wilczyńska I, Lianeri M, Jagodziński PP. Genetic variants in BRIP1 (BACH1) contribute to risk of nonsyndromic cleft lip with or without cleft palate. ACTA ACUST UNITED AC 2014; 100:670-8. [PMID: 25045080 DOI: 10.1002/bdra.23275] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 04/12/2014] [Accepted: 06/02/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND The etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) is very complex and still not well elucidated. Given the critical role of DNA damage repair in the embryonic development, we decided to test the hypothesis that polymorphisms of selected DNA repair genes might contribute to the risk of NSCL/P in the Polish population. METHODS Analysis of 36 polymorphisms in 12 DNA damage repair genes (ATM, BLM, BRCA1, BRIP1, E2F1, MLH1, MRE11A, MSH2, MSH6, NBN, RAD50, and RAD51) was conducted using TaqMan assays in a group of 263 NSCL/P patients and matched control group (n = 526). RESULTS Statistical analysis of genotyping results revealed that nucleotide variants in the BRIP1 (BACH1) gene were associated with the risk of NSCL/P. Under assumption of a dominant model, the calculated odds ratios (ORs) for BRIP1 rs8075370 and rs9897121 were 1.689 (95% confidence interval [CI], 1.249-2.282; p = 0.0006) and 1.621 (95% CI, 1.200-2.191; p = 0.0016), respectively. These results were statistically significant even after applying multiple testing correction. Additional evidence for a causative role of BRIP1 in NSCL/P etiology was provided by haplotype analysis. Borderline association with a decreased risk of this anomaly was also observed for BLM rs401549 (ORrecessive = 0.406; 95% CI, 0.223-1.739; p = 0.002) and E2F1 rs2071054 (ORdominant = 0.632; 95% CI, 0.469-0.852; p = 0.003). CONCLUSION Our study suggests that polymorphic variants of DNA damage repair genes play a role in the susceptibility to NSCL/P. BRIP1 might be novel candidate gene for this common developmental anomaly.
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Affiliation(s)
- Adrianna Mostowska
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland
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Leongamornlert D, Saunders E, Dadaev T, Tymrakiewicz M, Goh C, Jugurnauth-Little S, Kozarewa I, Fenwick K, Assiotis I, Barrowdale D, Govindasami K, Guy M, Sawyer E, Wilkinson R, The UKGPCS Collaborators, Antoniou AC, Eeles R, Kote-Jarai Z. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer 2014; 110:1663-72. [PMID: 24556621 PMCID: PMC3960610 DOI: 10.1038/bjc.2014.30] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Revised: 12/19/2013] [Accepted: 01/08/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and among the leading causes of cancer-related death. The purpose of this study was to use second-generation sequencing technology to assess the frequency of deleterious mutations in 22 tumour suppressor genes in familial PrCa and estimate the relative risk of PrCa if these genes are mutated. METHODS Germline DNA samples from 191 men with 3 or more cases of PrCa in their family were sequenced for 22 tumour suppressor genes using Agilent target enrichment and Illumina technology. Analysis for genetic variation was carried out by using a pipeline consisting of BWA, Genome Analysis Toolkit (GATK) and ANNOVAR. Clinical features were correlated with mutation status using standard statistical tests. Modified segregation analysis was used to determine the relative risk of PrCa conferred by the putative loss-of-function (LoF) mutations identified. RESULTS We discovered 14 putative LoF mutations in 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (P=0.00164). Segregation analysis of probands with European ancestry estimated that LoF mutations in any of the studied genes confer a relative risk of PrCa of 1.94 (95% CI: 1.56-2.42). CONCLUSIONS These findings show that LoF mutations in DNA repair pathway genes predispose to familial PrCa and advanced disease and therefore warrants further investigation. The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread.
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Affiliation(s)
- D Leongamornlert
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
| | - E Saunders
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
| | - T Dadaev
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
| | - M Tymrakiewicz
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
| | - C Goh
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
| | - S Jugurnauth-Little
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
| | - I Kozarewa
- Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK
| | - K Fenwick
- Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK
| | - I Assiotis
- Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK
| | - D Barrowdale
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - K Govindasami
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
| | - M Guy
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
| | - E Sawyer
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
| | - R Wilkinson
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
| | - The UKGPCS Collaborators
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
- Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK
| | - A C Antoniou
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - R Eeles
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
- The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK
| | - Z Kote-Jarai
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK
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Eeles R, Goh C, Castro E, Bancroft E, Guy M, Al Olama AA, Easton D, Kote-Jarai Z. The genetic epidemiology of prostate cancer and its clinical implications. Nat Rev Urol 2014; 11:18-31. [PMID: 24296704 DOI: 10.1038/nrurol.2013.266] [Citation(s) in RCA: 178] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Worldwide, familial and epidemiological studies have generated considerable evidence of an inherited component to prostate cancer. Indeed, rare highly penetrant genetic mutations have been implicated. Genome-wide association studies (GWAS) have also identified 76 susceptibility loci associated with prostate cancer risk, which occur commonly but are of low penetrance. However, these mutations interact multiplicatively, which can result in substantially increased risk. Currently, approximately 30% of the familial risk is due to such variants. Evaluating the functional aspects of these variants would contribute to our understanding of prostate cancer aetiology and would enable population risk stratification for screening. Furthermore, understanding the genetic risks of prostate cancer might inform predictions of treatment responses and toxicities, with the goal of personalized therapy. However, risk modelling and clinical translational research are needed before we can translate risk profiles generated from these variants into use in the clinical setting for targeted screening and treatment.
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Affiliation(s)
- Rosalind Eeles
- Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
| | - Chee Goh
- Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
| | - Elena Castro
- Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
| | - Elizabeth Bancroft
- Clinical Academic Cancer Genetics Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT, UK
| | - Michelle Guy
- Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
| | - Ali Amin Al Olama
- Cancer Research UK Centre for Cancer Genetic Epidemiology, Strangeways Laboratory, University of Cambridge, Cambridge CB1 8RN, UK
| | - Douglas Easton
- Departments of Public Health & Primary Care and Oncology, Strangeways Laboratory, University of Cambridge, Cambridge CB1 8RN, UK
| | - Zsofia Kote-Jarai
- Oncogenetics Team, Division of Cancer Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK
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A common nonsense mutation of the BLM gene and prostate cancer risk and survival. Gene 2013; 532:173-6. [PMID: 24096176 DOI: 10.1016/j.gene.2013.09.079] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 09/18/2013] [Accepted: 09/23/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Germline mutations of BRCA2 and NBS1 genes cause inherited recessive chromosomal instability syndromes and predispose to prostate cancer of poor prognosis. Mutations of the BLM gene cause another chromosomal instability clinical syndrome, called Bloom syndrome. Recently, a recurrent truncating mutation of BLM (Q548X) has been associated with a 6-fold increased risk of breast cancer in Russia, Belarus and Ukraine, but its role in prostate cancer etiology and survival has not been investigated yet. METHODS To establish whether the Q548X allele of the BLM gene is present in Poland, and whether this allele predisposes to poor prognosis prostate cancer, we genotyped 3337 men with prostate cancer and 2604 controls. RESULTS Q548X was detected in 13 of 3337 (0.4%) men with prostate cancer compared to 15 of 2604 (0.6%) controls (OR=0.7; 95% CI 0.3-1.4). A positive family history of any cancer in a first- or second-degree relative was seen only in 4 of the 13 (30%) mutation positive families, compared to 49% (1485/3001) of the non-carrier families (p=0.3). The mean follow-up was 49months. Survival was similar among carriers of Q548X and non-carriers (HR=1.1; p=0.9). The 5-year survival for men with a BLM mutation was 83%, compared to 72% for mutation-negative cases. CONCLUSIONS BLM Q548X is a common founder mutation in Poland. We found no evidence that this mutation predisposes one to prostate cancer or affect prostate cancer survival. However, based on the observed 0.6% population frequency of the Q548X allele, we estimate that one in 100,000 children should be affected by Bloom syndrome in Poland.
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The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol 2013; 14:882-92. [PMID: 23810788 DOI: 10.1016/s1470-2045(13)70240-7] [Citation(s) in RCA: 437] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. METHODS In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. FINDINGS Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8-46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. INTERPRETATION A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. FUNDING Merck Sharp and Dohme.
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Identification of a novel NBN truncating mutation in a family with hereditary prostate cancer. Fam Cancer 2013; 11:595-600. [PMID: 22864661 DOI: 10.1007/s10689-012-9555-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Nibrin (NBN), located on chromosome 8q21 is a gene involved in DNA double-strand break repair that has been implicated in the rare autosomal recessive chromosomal instability syndrome known as Nijmegen Breakage Syndrome (NBS). NBS is characterized by specific physical characteristics (microcephaly and dysmorphic facies), immunodeficiency, and increased risk of malignancy. Individuals who are heterozygous for NBN mutations are clinically asymptomatic, but may display an elevated risk for certain cancers including, but not limited to, ovarian and prostate cancer as well as various lymphoid malignancies. In this study, 94 unrelated familial prostate cancer cases from the University of Michigan Prostate Cancer Genetics Project (n = 54) and Johns Hopkins University (n = 40) were subjected to targeted next-generation sequencing of the exons, including UTRs, of NBN. One individual of European descent, diagnosed with prostate cancer at age 52, was identified to have a heterozygous 2117 C > G mutation in exon 14 of the gene, that results in a premature stop at codon 706 (S706X). Sequencing of germline DNA from additional male relatives showed partial co-segregation of the NBN S706X mutation with prostate cancer. This NBN mutation was not observed among 2768 unrelated European men (1859 with prostate cancer and 909 controls). NBN is involved in double-strand break repair as a component of the MRE11 (meiotic recombination 11)/RAD50/NBN genomic stability complex. The S706X mutation truncates the protein in a highly conserved region of NBN near the MRE11 binding site, thus suggesting a role for rare NBN mutations in prostate cancer susceptibility.
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BRIP1 variations analysis reveals their relative importance as genetic susceptibility factor for cervical cancer. Biochem Biophys Res Commun 2013; 433:232-6. [DOI: 10.1016/j.bbrc.2013.02.089] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Accepted: 02/27/2013] [Indexed: 12/24/2022]
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Abstract
It is clear that FANCJ, also known as BACH1 or BRIP1, is an essential tumor suppressor gene based on the identification of clinically relevant mutations not only in breast cancer, but also the childhood cancer syndrome, Fanconi anemia. This conclusion is further supported by the direct and functional interaction between FANCJ and the hereditary breast cancer-associated gene product BRCA1. In the absence of the FANCJ DNA helicase or its interaction with BRCA1, cells have defects in several aspects of the DNA damage response. In particular, the BRCA1-FANCJ interaction is essential for promoting error-free repair, checkpoint control and for limiting DNA damage tolerance. As the number of FANCJ clinical mutations and affected patients accumulate, it will be critical to understand whether the associated tumors resemble BRCA-associated tumors. If so, FANCJ patients could also benefit from new therapies that selectively sensitize DNA repair-defective tumors and spare healthy cells. In this article, we summarize the breast cancer-associated FANCJ mutations and discuss functional outcomes for DNA repair and tumor suppression.
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Affiliation(s)
- Sharon B Cantor
- Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605, USA.
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Yano K. Gene expression correlation analysis predicts involvement of high- and low-confidence risk genes in different stages of prostate carcinogenesis. Prostate 2010; 70:1746-59. [PMID: 20564324 DOI: 10.1002/pros.21210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Whole genome association studies have identified many loci associated with the risk of prostate cancer (PC). However, very few of the genes associated with these loci have been related to specific processes of prostate carcinogenesis. Therefore I inferred biological functions associated with these risk genes using gene expression correlation analysis. METHODS PC risk genes reported in the literature were classified as having high (P<10(-6)), medium (P<10(-4)), or low (P<10(-2)) statistical confidence. Correlation coefficients of the expression levels between the risk genes and other genes in cancerous prostates samples were compared against those in normal prostates using a microarray dataset from Gene Expression Omnibus. RESULTS Overall, significant decrease of correlations in PC was observed between the levels of expression of the high-confidence genes and other genes in the microarray dataset, whereas correlation between low-confidence genes and other genes in PC showed smaller decrease. Genes involved in developmental processes were significantly correlated with all risk gene categories. Ectoderm development genes, which may be related to squamous metaplasia, and genes enriched in fetal prostate stem cells (PSCs) showed strong association with the high-confidence genes. The association between the PSC genes and the low-confidence genes was weak, but genes related to neural system genes showed strong association with low-confidence genes. CONCLUSIONS The high-confidence risk genes may be associated with an early stage of prostate carcinogenesis, possibly involving PSCs and squamous metaplasia. The low-confidence genes may be involved in a later stage of carcinogenesis.
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Affiliation(s)
- Kojiro Yano
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
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Ray AM, Zuhlke KA, Johnson GR, Levin AM, Douglas JA, Lange EM, Cooney KA. Absence of truncating BRIP1 mutations in chromosome 17q-linked hereditary prostate cancer families. Br J Cancer 2009; 101:2043-7. [PMID: 19935797 PMCID: PMC2795448 DOI: 10.1038/sj.bjc.6605433] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: In a genome-wide scan (GWS) of 175 multiplex prostate cancer (PCa) families from the University of Michigan Prostate Cancer Genetics Project (PCGP), linkage was observed to markers on chromosome 17q21–24, a region that includes two breast cancer susceptibility genes, BRCA1 and BRIP1. BRIP1 is a Fanconi anaemia gene (FANCJ) that interacts with the BRCT domain of BRCA1 and has a role in DNA damage repair. Protein truncating mutations in BRIP1 have been identified in hereditary breast and ovarian cancer families, and a recent report suggested that a recurrent truncating mutation (R798X) may have a role in PCa susceptibility. Methods: We examined the role of BRIP1 mutations in hereditary PCa through sequence analysis of 94 individuals from PCGP families showing linkage to 17q. Results: A total of 24 single-nucleotide polymorphisms, including 7 missense variants but no protein truncating mutations, were observed. Conclusion: The data presented here suggest that BRIP1 truncating mutations are uncommon in PCa cases and do not account for the linkage to chromosome 17q observed in our GWS. Additional investigation is needed to determine the significance, if any, of the observed BRIP1 missense variants in hereditary PCa.
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Affiliation(s)
- A M Ray
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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Grindedal EM, Møller P, Eeles R, Stormorken AT, Bowitz-Lothe IM, Landrø SM, Clark N, Kvåle R, Shanley S, Maehle L. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev 2009; 18:2460-7. [PMID: 19723918 DOI: 10.1158/1055-9965.epi-09-0058] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Genetic predisposition to prostate cancer includes multiple common variants with a low penetrance (single nucleotide polymorphisms) and rare variants with higher penetrance. The mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 are associated with Lynch syndrome where colon and endometrial cancers are the predominant phenotypes. The purpose of our study was to investigate whether germ-line mutations in these genes may be associated with prostate cancer. One hundred and six male carriers or obligate carriers of MMR mutations were identified. Nine had contracted prostate cancer. Immunohistochemical analysis was done on tumor tissue from eight of the nine tumors. Observed incidence, cumulative risk at 60 and 70 years of age, age of onset, and Gleason score were compared with expected as assessed from population-based series. Absence of gene product from the mutated MMR gene was found in seven of eight tumors. Expected number of prostate cancers was 1.52 compared with 9 observed (P < 0.01). Mean age of onset of prostate cancer was 60.4 years compared with 66.6 expected (P = 0.006); the number of men with a Gleason score between 8 and 10 was significantly higher than expected (P < 0.00001). Kaplan-Meier analysis suggested that cumulative risk by 70 years in MMR mutation carriers may be 30% (SE, 0.088) compared with 8.0% in the general population. This is similar to the high risk associated with BRCA2 mutations. To our knowledge, this study is the first to indicate that the MMR genes may be among the rare genetic variants that confer a high risk of prostate cancer when mutated.
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Affiliation(s)
- Eli Marie Grindedal
- Section for Inherited Cancer, Department of Medical Genetics, Rikshospitalet University Hospital, N-0310 Oslo, Norway
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