|
1
|
Wei A, Border R, Fu B, Cullina S, Brandes N, Jang SK, Sankararaman S, Kenny EE, Udler MS, Ntranos V, Zaitlen N, Arboleda VA. Investigating the sources of variable impact of pathogenic variants in monogenic metabolic conditions. Nat Commun 2025; 16:5223. [PMID: 40473624 PMCID: PMC12141715 DOI: 10.1038/s41467-025-60339-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 05/20/2025] [Indexed: 06/11/2025] Open
Abstract
Over three percent of people carry a dominant pathogenic variant, yet only a fraction of carriers develop disease. Disease phenotypes from carriers of variants in the same gene range from mild to severe. Here, we investigate underlying mechanisms for this heterogeneity: variable variant effect sizes, carrier polygenic backgrounds, and modulation of carrier effect by genetic background (marginal epistasis). We leveraged exomes and clinical phenotypes from the UK Biobank and the Mt. Sinai BioMe Biobank to identify carriers of pathogenic variants affecting cardiometabolic traits. We employed recently developed methods to study these cohorts, observing strong statistical support and clinical translational potential for all three mechanisms of variable carrier penetrance and disease severity. For example, scores from our recent model of variant pathogenicity were tightly correlated with phenotype amongst clinical variant carriers, they predicted effects of variants of unknown significance, and they distinguished gain- from loss-of-function variants. We also found that polygenic scores modify phenotypes amongst pathogenic carriers and that genetic background additionally alters the effects of pathogenic variants through interactions.
Collapse
Affiliation(s)
- Angela Wei
- Interdepartmental Bioinformatics Program, UCLA, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Richard Border
- Department of Computer Science, UCLA, Los Angeles, CA, USA
- Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Boyang Fu
- Department of Computer Science, UCLA, Los Angeles, CA, USA
| | - Sinéad Cullina
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nadav Brandes
- Department of Epidemiology & Biostatistics, UCSF, San Francisco, CA, USA
- Department of Bioengineering & Therapeutic Sciences (HIVE), UCSF, San Francisco, CA, USA
- Bakar Computational Health Sciences Institute, UCSF, San Francisco, CA, USA
| | - Seon-Kyeong Jang
- Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Sriram Sankararaman
- Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Department of Computer Science, UCLA, Los Angeles, CA, USA
| | - Eimear E Kenny
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Translational Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam S Udler
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- The Broad Institute, Boston, MA, USA
| | - Vasilis Ntranos
- Department of Epidemiology & Biostatistics, UCSF, San Francisco, CA, USA
- Department of Bioengineering & Therapeutic Sciences (HIVE), UCSF, San Francisco, CA, USA
- Bakar Computational Health Sciences Institute, UCSF, San Francisco, CA, USA
| | - Noah Zaitlen
- Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Valerie A Arboleda
- Interdepartmental Bioinformatics Program, UCLA, Los Angeles, CA, USA.
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
- Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
- Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
| |
Collapse
|
|
2
|
Wei A, Border R, Fu B, Cullina S, Brandes N, Jang SK, Sankararaman S, Kenny E, Udler MS, Ntranos V, Zaitlen N, Arboleda V. Investigating the sources of variable impact of pathogenic variants in monogenic metabolic conditions. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2023.09.14.23295564. [PMID: 37745486 PMCID: PMC10516069 DOI: 10.1101/2023.09.14.23295564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Over three percent of people carry a dominant pathogenic variant, yet only a fraction of carriers develop disease. Disease phenotypes from carriers of variants in the same gene range from mild to severe. Here, we investigate underlying mechanisms for this heterogeneity: variable variant effect sizes, carrier polygenic backgrounds, and modulation of carrier effect by genetic background (marginal epistasis). We leveraged exomes and clinical phenotypes from the UK Biobank and the Mt. Sinai BioMe Biobank to identify carriers of pathogenic variants affecting cardiometabolic traits. We employed recently developed methods to study these cohorts, observing strong statistical support and clinical translational potential for all three mechanisms of variable carrier penetrance and disease severity. For example, scores from our recent model of variant pathogenicity were tightly correlated with phenotype amongst clinical variant carriers, they predicted effects of variants of unknown significance, and they distinguished gain- from loss-of-function variants. We also found that polygenic scores predicted phenotypes amongst pathogenic carriers and that epistatic effects can exceed main carrier effects by an order of magnitude.
Collapse
|
|
3
|
Sashittal P, Zhang H, Iacobuzio-Donahue CA, Raphael BJ. ConDoR: tumor phylogeny inference with a copy-number constrained mutation loss model. Genome Biol 2023; 24:272. [PMID: 38037115 PMCID: PMC10688497 DOI: 10.1186/s13059-023-03106-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 11/07/2023] [Indexed: 12/02/2023] Open
Abstract
A tumor contains a diverse collection of somatic mutations that reflect its past evolutionary history and that range in scale from single nucleotide variants (SNVs) to large-scale copy-number aberrations (CNAs). However, no current single-cell DNA sequencing (scDNA-seq) technology produces accurate measurements of both SNVs and CNAs, complicating the inference of tumor phylogenies. We introduce a new evolutionary model, the constrained k-Dollo model, that uses SNVs as phylogenetic markers but constrains losses of SNVs according to clusters of cells. We derive an algorithm, ConDoR, that infers phylogenies from targeted scDNA-seq data using this model. We demonstrate the advantages of ConDoR on simulated and real scDNA-seq data.
Collapse
Affiliation(s)
| | - Haochen Zhang
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, NY, USA
| | - Christine A Iacobuzio-Donahue
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, NY, USA
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, NY, USA
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, NY, USA
| | | |
Collapse
|
|
4
|
Ueki A, Yoshida R, Kosaka T, Matsubayashi H. Clinical risk management of breast, ovarian, pancreatic, and prostatic cancers for BRCA1/2 variant carriers in Japan. J Hum Genet 2023; 68:517-526. [PMID: 37088789 DOI: 10.1038/s10038-023-01153-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/21/2023] [Accepted: 04/13/2023] [Indexed: 04/25/2023]
Abstract
Opportunities for genetic counseling and germline BRCA1/2 (BRCA) testing are increasing in Japan owing to cancer genomic profiling testing and companion diagnostics being covered by national health insurance for patients with BRCA-related cancers. These tests are useful not only to judge whether platinum agents and PARP inhibitors are indicated but also to reveal an autosomal-dominant inherited cancer syndrome: hereditary breast and ovarian cancer. In individuals with germline BRCA variants, risk of cancers of the breast, ovary, pancreas, and prostate is significantly increased at various ages of onset, but the stomach, uterus, biliary tract, and skin might also be at risk. For women with pathogenic BRCA variants, breast awareness and image analyses should be initiated in their 20s, and risk-reducing procedures such as mastectomy are recommended starting in their 30s, with salpingo-oophorectomy in their late 30s. For male BRCA pathogenic variant carriers, prostatic surveillance should be applied using serum prostate-specific antigen starting in their 40s. For both sexes, image examinations ideally using endoscopic ultrasound and magnetic resonance cholangiopancreatography and blood testing should begin in their 50s for pancreatic surveillance. Homologous recombination pathway-associated genes are also causative candidates. Variant pathogenicity needs to be evaluated every 6-12 months when results are uncertain for clinical significance. Genetic counseling needs to be offered to the blood relatives of the pathogenic variant carriers with suitable timing. We review the recommended cross-organ BRCA risk management in Japan.
Collapse
Affiliation(s)
- Arisa Ueki
- Department of Clinical Genetics, The Cancer Institute Hospital of JFCR, 3-8-31, Ariake, Koto, Tokyo, 135-8550, Japan
| | - Reiko Yoshida
- Institute for Clinical Genetics and Genomics, Showa University, 1-5-8 Hatanodai Shinagawa-ku, Tokyo, 142-8555, Japan
| | - Takeo Kosaka
- Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroyuki Matsubayashi
- Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka, 411-8777, Japan.
| |
Collapse
|
|
5
|
Loboda AP, Adonin LS, Zvereva SD, Guschin DY, Korneenko TV, Telegina AV, Kondratieva OK, Frolova SE, Pestov NB, Barlev NA. BRCA Mutations-The Achilles Heel of Breast, Ovarian and Other Epithelial Cancers. Int J Mol Sci 2023; 24:ijms24054982. [PMID: 36902416 PMCID: PMC10003548 DOI: 10.3390/ijms24054982] [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: 02/11/2023] [Revised: 02/27/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Two related tumor suppressor genes, BRCA1 and BRCA2, attract a lot of attention from both fundamental and clinical points of view. Oncogenic hereditary mutations in these genes are firmly linked to the early onset of breast and ovarian cancers. However, the molecular mechanisms that drive extensive mutagenesis in these genes are not known. In this review, we hypothesize that one of the potential mechanisms behind this phenomenon can be mediated by Alu mobile genomic elements. Linking mutations in the BRCA1 and BRCA2 genes to the general mechanisms of genome stability and DNA repair is critical to ensure the rationalized choice of anti-cancer therapy. Accordingly, we review the literature available on the mechanisms of DNA damage repair where these proteins are involved, and how the inactivating mutations in these genes (BRCAness) can be exploited in anti-cancer therapy. We also discuss a hypothesis explaining why breast and ovarian epithelial tissues are preferentially susceptible to mutations in BRCA genes. Finally, we discuss prospective novel therapeutic approaches for treating BRCAness cancers.
Collapse
Affiliation(s)
- Anna P. Loboda
- Laboratory of Molecular Oncology, Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
| | | | - Svetlana D. Zvereva
- Laboratory of Molecular Oncology, Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
| | - Dmitri Y. Guschin
- School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan
| | - Tatyana V. Korneenko
- Group of Cross-Linking Enzymes, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
| | | | | | | | - Nikolay B. Pestov
- Institute of Biomedical Chemistry, 119121 Moscow, Russia
- Group of Cross-Linking Enzymes, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, 108819 Moscow, Russia
- Correspondence: (N.B.P.); (N.A.B.)
| | - Nick A. Barlev
- Institute of Biomedical Chemistry, 119121 Moscow, Russia
- School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan
- Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, 108819 Moscow, Russia
- Institute of Cytology, Tikhoretsky ave 4, 194064 St-Petersburg, Russia
- Correspondence: (N.B.P.); (N.A.B.)
| |
Collapse
|
|
6
|
Sashittal P, Zhang H, Iacobuzio-Donahue CA, Raphael BJ. ConDoR: Tumor phylogeny inference with a copy-number constrained mutation loss model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.05.522408. [PMID: 36711528 PMCID: PMC9882003 DOI: 10.1101/2023.01.05.522408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Tumors consist of subpopulations of cells that harbor distinct collections of somatic mutations. These mutations range in scale from single nucleotide variants (SNVs) to large-scale copy-number aberrations (CNAs). While many approaches infer tumor phylogenies using SNVs as phylogenetic markers, CNAs that overlap SNVs may lead to erroneous phylogenetic inference. Specifically, an SNV may be lost in a cell due to a deletion of the genomic segment containing the SNV. Unfortunately, no current single-cell DNA sequencing (scDNA-seq) technology produces accurate measurements of both SNVs and CNAs. For instance, recent targeted scDNA-seq technologies, such as Mission Bio Tapestri, measure SNVs with high fidelity in individual cells, but yield much less reliable measurements of CNAs. We introduce a new evolutionary model, the constrained k-Dollo model, that uses SNVs as phylogenetic markers and partial information about CNAs in the form of clustering of cells with similar copy-number profiles. This copy-number clustering constrains where loss of SNVs can occur in the phylogeny. We develop ConDoR (Constrained Dollo Reconstruction), an algorithm to infer tumor phylogenies from targeted scDNA-seq data using the constrained k-Dollo model. We show that ConDoR outperforms existing methods on simulated data. We use ConDoR to analyze a new multi-region targeted scDNA-seq dataset of 2153 cells from a pancreatic ductal adenocarcinoma (PDAC) tumor and produce a more plausible phylogeny compared to existing methods that conforms to histological results for the tumor from a previous study. We also analyze a metastatic colorectal cancer dataset, deriving a more parsimonious phylogeny than previously published analyses and with a simpler monoclonal origin of metastasis compared to the original study. Code availability Software is available at https://github.com/raphael-group/constrained-Dollo.
Collapse
Affiliation(s)
| | - Haochen Zhang
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, NY, USA
| | - Christine A. Iacobuzio-Donahue
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, NY, USA
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, NY, USA
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, NY, USA
| | | |
Collapse
|
|
7
|
Liang JW, Idos GE, Hong C, Gruber SB, Parmigiani G, Braun D. Statistical methods for Mendelian models with multiple genes and cancers. Genet Epidemiol 2022; 46:395-414. [PMID: 35583099 PMCID: PMC9452449 DOI: 10.1002/gepi.22460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 04/06/2022] [Accepted: 05/05/2022] [Indexed: 01/29/2023]
Abstract
Risk evaluation to identify individuals who are at greater risk of cancer as a result of heritable pathogenic variants is a valuable component of individualized clinical management. Using principles of Mendelian genetics, Bayesian probability theory, and variant-specific knowledge, Mendelian models derive the probability of carrying a pathogenic variant and developing cancer in the future, based on family history. Existing Mendelian models are widely employed, but are generally limited to specific genes and syndromes. However, the upsurge of multigene panel germline testing has spurred the discovery of many new gene-cancer associations that are not presently accounted for in these models. We have developed PanelPRO, a flexible, efficient Mendelian risk prediction framework that can incorporate an arbitrary number of genes and cancers, overcoming the computational challenges that arise because of the increased model complexity. We implement an 11-gene, 11-cancer model, the largest Mendelian model created thus far, based on this framework. Using simulations and a clinical cohort with germline panel testing data, we evaluate model performance, validate the reverse-compatibility of our approach with existing Mendelian models, and illustrate its usage. Our implementation is freely available for research use in the PanelPRO R package.
Collapse
Affiliation(s)
- Jane W. Liang
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA, Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Gregory E. Idos
- Center for Precision Medicine, City of Hope, Duarte, CA, USA
| | - Christine Hong
- Center for Precision Medicine, City of Hope, Duarte, CA, USA
| | | | - Giovanni Parmigiani
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA, Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Danielle Braun
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA, Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| |
Collapse
|
|
8
|
Abstract
Background It is estimated that about 10% of pancreatic cancer cases have a genetic background. People with a familial predisposition to pancreatic cancer can be divided into 2 groups. The first is termed hereditary pancreatic cancer, which occurs in individuals with a known hereditary cancer syndrome caused by germline single gene mutations (e.g., BRCA1/2, CDKN2A). The second is considered as familial pancreatic cancer, which is associated with several genetic factors responsible for the more common development of pancreatic cancer in certain families, but the precise single gene mutation has not been found. Aim This review summarizes the current state of knowledge regarding the risk of pancreatic cancer development in hereditary pancreatic cancer and familial pancreatic cancer patients. Furthermore, it gathers the latest recommendations from the three major organizations dealing with the prevention of pancreatic cancer in high-risk groups and explores recent guidelines of scientific societies on screening for pancreatic cancers in individuals at risk for hereditary or familial pancreatic cancer. Conclusions In order to improve patients’ outcomes, authors of current guidelines recommend early and intensive screening in patients with pancreatic cancer resulting from genetic background. The screening should be performed in excellence centers. The scope, extent and cost-effectiveness of such interventions requires further studies.
Collapse
|
|
9
|
Devico Marciano N, Kroening G, Dayyani F, Zell JA, Lee FC, Cho M, Valerin JG. BRCA-Mutated Pancreatic Cancer: From Discovery to Novel Treatment Paradigms. Cancers (Basel) 2022; 14:cancers14102453. [PMID: 35626055 PMCID: PMC9140002 DOI: 10.3390/cancers14102453] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/02/2022] [Accepted: 05/13/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Approximately 10–20% of pancreatic cancer patients will have a mutation in their DNA, passed on in families, that contributes to the development of their pancreatic cancer. These mutations are important in that they effect the biology of the disease as well as contribute to sensitivity to specific treatments. We describe the critical role that these genes play in various cellular processes in the body that contribute to their role in cancer development and normal cellular function. In this review, we aim to describe the role of certain genes (BRCA1 and BRCA2) in the development of pancreatic cancer and the current and future research efforts underway to treat this subtype of disease. Abstract The discovery of BRCA1 and BRCA2 in the 1990s revolutionized the way we research and treat breast, ovarian, and pancreatic cancers. In the case of pancreatic cancers, germline mutations occur in about 10–20% of patients, with mutations in BRCA1 and BRCA2 being the most common. BRCA genes are critical in DNA repair pathways, particularly in homologous recombination, which has a serious impact on genomic stability and can contribute to cancerous cell proliferation. However, BRCA1 also plays a fundamental role in cell cycle checkpoint control, ubiquitination, control of gene expression, and chromatin remodeling, while BRCA2 also plays a role in transcription and immune system response. Therefore, mutations in these genes lead to multiple defects in cells that may be utilized when treating cancer. BRCA mutations seem to confer a prognostic benefit with an improved overall survival due to differing underlying biology. These mutations also appear to be a predictive marker, with patients showing increased sensitivity to certain treatments, such as platinum chemotherapy and PARP inhibitors. Olaparib is currently indicated for maintenance therapy in metastatic PDAC after induction with platinum-based chemotherapy. Resistance has been found to these therapies, and with a 10.8% five-year OS, novel therapies are desperately needed.
Collapse
|
|
10
|
Subhan A, Attia SA, P Torchilin V. Targeted siRNA nanotherapeutics against breast and ovarian metastatic cancer: a comprehensive review of the literature. Nanomedicine (Lond) 2021; 17:41-64. [PMID: 34930021 DOI: 10.2217/nnm-2021-0207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Metastasis is considered the major cause of unsuccessful cancer therapy. The metastatic development requires tumor cells to leave their initial site, circulate in the blood stream, acclimate to new cellular environments at a remote secondary site and endure there. There are several steps in metastasis, including invasion, intravasation, circulation, extravasation, premetastatic niche formation, micrometastasis and metastatic colonization. siRNA therapeutics are appreciated for their usefulness in treatment of cancer metastasis. However, siRNA therapy as a single therapy may not be a sufficient option for control of metastasis. By combining siRNA with targeting, functional agents or small-molecule drugs have shown potential effects that enhance therapeutic effectiveness. This review addresses multidrug resistance and metastasis in breast and ovarian cancers and highlights drug-delivery strategies using siRNA therapeutics.
Collapse
Affiliation(s)
- Abdus Subhan
- Department of Chemistry, ShahJalal University of Science & Technology, Sylhet 3114, Bangladesh
| | - Sara Aly Attia
- Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA
| | - Vladimir P Torchilin
- Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.,Department of Oncology, Radiotherapy & Plastic Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia
| |
Collapse
|
|
11
|
Guan B, Liang Y, Lu H, Xu Z, Shi Y, Li J, Kong W, Tian C, Tan Y, Gong Y, Liu J, Fang D, Shen Q, He S, Shakeel M, Zhang Z, He Q, Li X, Ci W, Zhou L. Copy Number Signatures and Clinical Outcomes in Upper Tract Urothelial Carcinoma. Front Cell Dev Biol 2021; 9:713499. [PMID: 34513842 PMCID: PMC8427613 DOI: 10.3389/fcell.2021.713499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 08/02/2021] [Indexed: 11/15/2022] Open
Abstract
Tumor staging of upper tract urothelial carcinomas (UTUCs) is relatively difficult to assert accurately before surgery. Here, we used copy number (CN) signatures as a tool to explore their clinical significance of molecular stratification in UTUC. CN signatures were extracted by non-negative matrix factorization from the whole-genome sequencing (WGS) data of 90 Chinese UTUC primary tumor samples. A validation UTUC cohort (n = 56) and a cohort from urinary cell-free DNA (cfDNA) of urothelial cancer patients (n = 94) and matched primary tumors were also examined. Survival analyses were measured using the Kaplan–Meier, and Cox regression was used for multivariate analysis. Here, we identified six CN signatures (Sig1–6). Patients with a high contribution of Sig6 (Sig6high) were associated with higher microsatellite instability level and papillary architecture and had a favorable outcome. Patients with a low weighted genome integrity index were associated with positive lymph node and showed the worst outcome. Sig6high was identified to be an independently prognostic factor. The predictive significance of CN signature was identified by a validation UTUC cohort. CN signatures retained great concordance between primary tumor and urinary cfDNA. In conclusion, our results reveal that CN signature assessment for risk stratification is feasible and provides a basis for clinical studies that evaluate therapeutic interventions and prognosis.
Collapse
Affiliation(s)
- Bao Guan
- Department of Urology, Peking University First Hospital, Beijing, China.,Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, National Urological Cancer Center, Beijing, China
| | - Yuan Liang
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Huan Lu
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Zhengzheng Xu
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yue Shi
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Juan Li
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Wenwen Kong
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Chuanyu Tian
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yezhen Tan
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yanqing Gong
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, National Urological Cancer Center, Beijing, China
| | - Jin Liu
- Department of Urology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Dong Fang
- Department of Urology, Peking University First Hospital, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, National Urological Cancer Center, Beijing, China
| | - Qi Shen
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, National Urological Cancer Center, Beijing, China
| | - Shiming He
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, National Urological Cancer Center, Beijing, China
| | - Muhammad Shakeel
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,Jamil-ur-Rahman Center for Genome Research, PCMD, ICCBS, University of Karachi, Karachi, Pakistan
| | - Zhongyuan Zhang
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, National Urological Cancer Center, Beijing, China
| | - Qun He
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, National Urological Cancer Center, Beijing, China
| | - Xuesong Li
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, National Urological Cancer Center, Beijing, China
| | - Weimin Ci
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute of Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Liqun Zhou
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, National Urological Cancer Center, Beijing, China
| |
Collapse
|
|
12
|
Shelemey PT, Amaro CP, Ng D, Falck V, Tam VC. Metastatic pancreatic cancer with complete response to FOLFIRINOX treatment. BMJ Case Rep 2021; 14:14/5/e238395. [PMID: 34031062 DOI: 10.1136/bcr-2020-238395] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
A 59-year-old woman presented with abdominal pain associated with nausea and night sweats. A large mass was found in the pancreatic tail and innumerable liver lesions were identified. Ultrasound-guided biopsy of a liver nodule confirmed moderately differentiated adenocarcinoma consistent with a pancreatobiliary primary. On FOLFIRINOX chemotherapy, subsequent CT scans showed shrinkage of the pancreatic mass and liver metastases. Her cancer antigen 19-9 (CA 19-9) normalised after 11 months. Oxaliplatin was discontinued due to peripheral neuropathy but she completed 37 cycles of FOLFIRI during which her pancreatic mass disappeared, liver lesions decreased in size and were subsequently deemed to be scar tissue by the radiologist. After 4 years of treatment, the patient agreed to a break from chemotherapy. Eighteen months afterwards, an MRI abdomen continues to demonstrate no visible pancreatic mass and the two remaining liver lesions, believed to be scar tissue, remain stable. Her CA 19-9 level remains normal. This appears to be a complete response to FOLFIRINOX/FOLFIRI chemotherapy in a patient with metastatic pancreatic cancer.
Collapse
Affiliation(s)
- Paige T Shelemey
- Medicine, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Carla P Amaro
- Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
| | - Danny Ng
- Radiology, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada
| | - Vincent Falck
- Pathology and Laboratory Medicine, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada
| | - Vincent C Tam
- Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada
| |
Collapse
|
|
13
|
Rahnamay Farnood P, Danesh Pazhooh R, Asemi Z, Yousefi B. DNA damage response and repair in pancreatic cancer development and therapy. DNA Repair (Amst) 2021; 103:103116. [PMID: 33882393 DOI: 10.1016/j.dnarep.2021.103116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 04/06/2021] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer (PC) is among fatal malignancies, with a dismal prognosis and a low survival rate of 5-10%. In both sporadic and inherited PC, gene alterations, such as BRCA1/2, PALB2, and ATM, can occur frequently. Currently, surgery, chemo- and radio-therapy are the most common therapeutic strategies for treating this cancer. DNA damage response (DDR) establishes multiple pathways that eliminate DNA damage sites to maintain genomic integrity. Various types of cancers and age-related diseases are associated with DDR machinery defects. According to the severity of the damage, DDR pathways respond appropriately to lesions through repairing damage, arresting the cell cycle, or apoptosis. Recently, novel agents, particularly those targeting DDR pathways, are being utilized to improve the response of many cancers to chemotherapy and radiotherapy. In this paper, we briefly reviewed DDR processes and their components, including DDR sensors, DDR mediators, and DDR transducers in the progression, prognosis, and treatment of PC.
Collapse
Affiliation(s)
| | | | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
14
|
Kim SH, Hwang HK, Lee WJ, Kang CM. Biologic behavior of resected BRCA-mutated pancreatic cancer: Comparison with sporadic pancreatic cancer and other BRCA-related cancers. Pancreatology 2021; 21:544-549. [PMID: 33612442 DOI: 10.1016/j.pan.2021.02.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 01/23/2021] [Accepted: 02/09/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Since margin-negative resection is essential for the cure of pancreatic cancer (PC), early detection of PC is important. Although PC is the third most common cancer associated with BRCA1/2 mutations, clinical research regarding BRCA mutations in resected PC are rare. In this study, we investigated the oncologic characteristics of resected PC with BRCA mutation to suggest management strategies. METHODS We retrospectively reviewed data from 493 patients who were confirmed to be pathogenic BRCA1/2 mutation carriers between January 2007 and December 2019. We investigated the oncologic characteristics of PC patients by comparing them with resected sporadic PC and other BRCA-related cancer groups (breast cancer, ovarian cancer, and others). RESULTS Ten BRCA mutation carriers (2.0%) experienced PC, and PC onset was significantly later than that of BRCA-related breast cancer (age: breast vs. pancreas, 45.0 vs. 53.5 years, p = 0.050). Six patients underwent pancreatectomy and their long-term survival outcomes did not differ from those of sporadic PC patients (disease free survival: BRCA1/2 vs. sporadic, 10.0 months vs. 9.0 months, p = 0.504; overall survival: BRCA1/2 vs. sporadic, 29.0 months vs. 35.0 months, p = 0.520). CONCLUSION BRCA-mutated PC occurs later than BRCA-mutated breast cancer. Active genetic testing to identify BRCA1/2 mutation carriers at the onset of breast cancer and continuous long-term surveillance of these patients can provide opportunities to detect BRCA-mutated PC at a resectable stage.
Collapse
Affiliation(s)
- Sung Hyun Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea; Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea
| | - Ho Kyoung Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea; Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea
| | - Woo Jung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea; Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea
| | - Chang Moo Kang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea; Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea.
| |
Collapse
|
|
15
|
Kane LE, Mellotte GS, Conlon KC, Ryan BM, Maher SG. Multi-Omic Biomarkers as Potential Tools for the Characterisation of Pancreatic Cystic Lesions and Cancer: Innovative Patient Data Integration. Cancers (Basel) 2021; 13:769. [PMID: 33673153 PMCID: PMC7918773 DOI: 10.3390/cancers13040769] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/27/2021] [Accepted: 02/09/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is regarded as one of the most lethal malignant diseases in the world, with GLOBOCAN 2020 estimates indicating that PC was responsible for almost half a million deaths worldwide in 2020. Pancreatic cystic lesions (PCLs) are fluid-filled structures found within or on the surface of the pancreas, which can either be pre-malignant or have no malignant potential. While some PCLs are found in symptomatic patients, nowadays many PCLs are found incidentally in patients undergoing cross-sectional imaging for other reasons-so called 'incidentalomas'. Current methods of characterising PCLs are imperfect and vary hugely between institutions and countries. As such, there is a profound need for improved diagnostic algorithms. This could facilitate more accurate risk stratification of those PCLs that have malignant potential and reduce unnecessary surveillance. As PC continues to have such a poor prognosis, earlier recognition and risk stratification of PCLs may lead to better treatment protocols. This review will focus on the importance of biomarkers in the context of PCLs and PCand outline how current 'omics'-related work could contribute to the identification of a novel integrated biomarker profile for the risk stratification of patients with PCLs and PC.
Collapse
Affiliation(s)
- Laura E. Kane
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin D08 W9RT, Ireland;
| | - Gregory S. Mellotte
- Department of Gastroenterology, Tallaght University Hospital, Dublin D24 NR0A, Ireland; (G.S.M.); (B.M.R.)
| | - Kevin C. Conlon
- Discipline of Surgery, School of Medicine, Trinity College Dublin, Dublin D02 PN40, Ireland;
| | - Barbara M. Ryan
- Department of Gastroenterology, Tallaght University Hospital, Dublin D24 NR0A, Ireland; (G.S.M.); (B.M.R.)
| | - Stephen G. Maher
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin D08 W9RT, Ireland;
| |
Collapse
|
|
16
|
Yang G, Yin J, Ou K, Du Q, Ren W, Jin Y, Peng L, Yang L. Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas harboring KRAS and BRCA mutations: case report and whole exome sequencing analysis. BMC Gastroenterol 2020; 20:202. [PMID: 32590950 PMCID: PMC7318525 DOI: 10.1186/s12876-020-01351-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 06/17/2020] [Indexed: 12/12/2022] Open
Abstract
Background Undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) is an extremely uncommon pancreatic neoplasm that comprises less than 1% of all exocrine pancreatic tumors. To date, cases and data from whole-exome sequencing (WES) analysis have been reported by specific studies. We report a case of pancreatic UC-OGC with a literature review, and provide novel insights into the molecular characteristics of this tumor entity. Case presentation A 31-year-old male presented with intermittent abdominal pain for several months, and positron emission tomography (PET) showed isolated high metabolic nodules during the pancreatic uncinate process that were likely to be malignant disease. Pathological examination after radical excision revealed UC-OGC associated with poorly differentiated adenocarcinoma at the head of the pancreas. The disease recurred 7.4 months after radical surgery. The KRAS p.G12D (c.35G > A) and somatic BRCA2 p.R2896C (c.8686C > T) mutations were detected by subsequent WES analysis. The patient showed no response to platinum-based systemic chemotherapy, and his condition quickly worsened. He finally died, with an overall survival of 1 year. Conclusions As an extremely uncommon tumor entity, UC-OGC is really a unique variant of conventional pancreatic ductal adenocarcinoma due to its similarities, as shown by genomic WES analysis. Clinical examination and molecular analysis by WES could further indicate potential treatment strategies for UC-OGC.
Collapse
Affiliation(s)
- Guangjian Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiangxia Yin
- Department of Oncology, Shouguang Hospital of Traditional Chinese Medicine, Weifang, 262700, China
| | - Kai Ou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qiang Du
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wenhao Ren
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yujing Jin
- Department of Medical Imaging, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Liming Peng
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lin Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| |
Collapse
|
|
17
|
Singh AK, Yu X. Tissue-Specific Carcinogens as Soil to Seed BRCA1/2-Mutant Hereditary Cancers. Trends Cancer 2020; 6:559-568. [PMID: 32336659 DOI: 10.1016/j.trecan.2020.03.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/05/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023]
Abstract
Despite their ubiquitous expression, the inheritance of monoallelic germline mutations in breast cancer susceptibility gene type 1 or 2 (BRCA1/2) poses tissue-specific variations in cancer risks and primarily associate with familial breast and ovarian cancers. The molecular basis of this tissue-specific tumor incidence remains unknown and intriguing to cancer researchers. A plethora of recent reports support the idea that several nongenetic factors present in the tissue microenvironment could induce tumors in the mutant BRCA1/2 background. This Opinion article summarizes the recent advances on tissue-specific carcinogens and their complex crosstalk with the compromised DNA repair machinery of BRCA1/2-mutant cells. Finally, we present our perspective on the therapeutic and chemopreventive interpretations of these developments.
Collapse
Affiliation(s)
- Anup Kumar Singh
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Xiaochun Yu
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
| |
Collapse
|
|
18
|
Cao CX, Sharib JM, Blanco AM, Goldberg D, Bracci P, Mukhtar RA, Esserman LJ, Kirkwood KS. Abdominal Imaging of Pancreatic Cysts and Cyst-Associated Pancreatic Cancer in BRCA1/2 Mutation Carriers: A Retrospective Cross-Sectional Study. J Am Coll Surg 2019; 230:53-63.e1. [PMID: 31672679 DOI: 10.1016/j.jamcollsurg.2019.09.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/30/2019] [Accepted: 09/16/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Direct-to-consumer BRCA testing will increase BRCA diagnoses and subsequent abdominal imaging. It is unclear whether BRCA carriers are at higher risk of developing pancreatic cysts (PCs) or cyst-associated pancreatic ductal adenocarcinoma (PDAC). We investigated the prevalence of PCs in BRCA-tested patients, and whether BRCA-carriers have higher rates of PDAC when PCs are found. STUDY DESIGN This is a retrospective cross-sectional study of patients with BRCA testing and abdominal imaging between 1996 and 2018. Pancreatic cysts were identified on original imaging reports. Prevalence and risk characteristics of PCs, as well as incidence of PDAC, were compared between BRCA+, BRCA-, and BRCA-untested patients. RESULTS Pancreatic cysts were identified in 4,045 patients among 128,164 unique patients with abdominal imaging, including 33 patients with PCs in 1,113 BRCA-tested patients. There was no difference in PC prevalence between BRCA+, BRCA-, and untested patients (3.6%, 2.6%, 3.2%, respectively; p = 0.64). Pancreatic cysts were diagnosed in BRCA+ patients at a younger age (57.1 vs 65.3 years, p < 0.001); however, there was no difference in risk stratification compared with BRCA- or untested patients by consensus criteria. Across the population of imaged patients, patients with PCs had significantly higher rates of PDAC compared with those without PCs (18.2% vs 2.4%, p < 0.001). Incidence of cyst-associated PDAC was similar in BRCA+ and BRCA- patients (13.3% vs 22.2%, p = 0.84). CONCLUSIONS BRCA+ patients have similar rates of PCs, high-risk features in their cysts, and PDAC as BRCA- and untested patients. BRCA+ patients likely do not require dedicated abdominal imaging to evaluate for PCs and should follow management guidelines similar to those as the untested general population if an incidental PC is identified.
Collapse
Affiliation(s)
- Carrie X Cao
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | - Jeremy M Sharib
- Department of Surgery, University of California San Francisco, San Francisco, CA.
| | - Amie M Blanco
- University of California San Francisco Cancer Genetics and Prevention Program, San Francisco, CA; University of California San Francisco Heller Diller Family Comprehensive Cancer Center, San Francisco, CA
| | - Dena Goldberg
- University of California San Francisco Cancer Genetics and Prevention Program, San Francisco, CA
| | - Paige Bracci
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA
| | - Rita A Mukhtar
- Department of Surgery, University of California San Francisco, San Francisco, CA; University of California San Francisco Heller Diller Family Comprehensive Cancer Center, San Francisco, CA
| | - Laura J Esserman
- Department of Surgery, University of California San Francisco, San Francisco, CA; University of California San Francisco Heller Diller Family Comprehensive Cancer Center, San Francisco, CA
| | - Kimberly S Kirkwood
- Department of Surgery, University of California San Francisco, San Francisco, CA; University of California San Francisco Heller Diller Family Comprehensive Cancer Center, San Francisco, CA
| |
Collapse
|
|
19
|
Fong CYK, Burke E, Cunningham D, Starling N. Up-to-Date Tailored Systemic Treatment in Pancreatic Ductal Adenocarcinoma. Gastroenterol Res Pract 2019; 2019:7135437. [PMID: 31582971 PMCID: PMC6748185 DOI: 10.1155/2019/7135437] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/09/2019] [Indexed: 12/24/2022] Open
Abstract
Despite intensive research efforts, pancreatic ductal adenocarcinoma is still regarded as an aggressive and life-limiting malignancy. Combination chemotherapy regimens that underpin the current treatment approach in the advanced setting have led to incremental survival gains in recent years but have failed to confer patients with a median overall survival that exceeds 12 months from diagnosis. Research has since focussed on understanding the role and interplay between various components of the desmoplastic stroma and tumour microenvironment, in addition to developing targeted therapies based on molecular features to improve the prognosis associated with this malignancy. This review will summarise the available systemic treatment options and discuss potential methods to refine the resolution of patient selection to enhance responses to currently available therapies. Furthermore, it will explore newer approaches anticipated to come to the fore of future clinical practice, such as agents targeting the DNA damage response and tumour microenvironment as well as immunotherapy-based combinations.
Collapse
Affiliation(s)
| | - Emma Burke
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK
| | - David Cunningham
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK
| | - Naureen Starling
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK
| |
Collapse
|
|
20
|
Obazee O, Archibugi L, Andriulli A, Soucek P, Małecka-Panas E, Ivanauskas A, Johnson T, Gazouli M, Pausch T, Lawlor RT, Cavestro GM, Milanetto AC, Di Leo M, Pasquali C, Hegyi P, Szentesi A, Radu CE, Gheorghe C, Theodoropoulos GE, Bergmann F, Brenner H, Vodickova L, Katzke V, Campa D, Strobel O, Kaiser J, Pezzilli R, Federici F, Mohelnikova-Duchonova B, Boggi U, Lemstrova R, Johansen JS, Bojesen SE, Chen I, Jensen BV, Capurso G, Pazienza V, Dervenis C, Sperti C, Mambrini A, Hackert T, Kaaks R, Basso D, Talar-Wojnarowska R, Maiello E, Izbicki JR, Cuk K, Saum KU, Cantore M, Kupcinskas J, Palmieri O, Delle Fave G, Landi S, Salvia R, Fogar P, Vashist YK, Scarpa A, Vodicka P, Tjaden C, Iskierka-Jazdzewska E, Canzian F. Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma. Int J Cancer 2019; 145:686-693. [PMID: 30672594 DOI: 10.1002/ijc.32127] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 11/23/2018] [Accepted: 12/05/2018] [Indexed: 02/05/2023]
Abstract
Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.
Collapse
Affiliation(s)
- O Obazee
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - L Archibugi
- Digestive and Liver Disease Unit, Pancreatic Disorders Clinic, S. Andrea Hospital, University of Sapienza, Rome, Italy
- Pancreatico/Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - A Andriulli
- Division of Gastroenterology and Research Laboratory, Department of Oncology, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - P Soucek
- Laboratory of Pharmacogenomics, Biomedical Centre, Faculty of Medicine in Plzen, Charles University in Prague, Plzen, Czech Republic
| | - E Małecka-Panas
- Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | - A Ivanauskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - T Johnson
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - M Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School National and Kapodistrian University of Athens, Athens, Greece
| | - T Pausch
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Germany
| | - R T Lawlor
- ARC-Net, Applied Research on Cancer Centre, University of Verona, Verona, Italy
| | - G M Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - A C Milanetto
- Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Padova, Italy
| | - M Di Leo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - C Pasquali
- Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Padova, Italy
| | - P Hegyi
- Institute for Translational Medicine and 1st Department of Medicine, University of Pécs, Pécs, Hungary
| | - A Szentesi
- Institute for Translational Medicine and 1st Department of Medicine, University of Pécs, Pécs, Hungary
| | - C E Radu
- Fundeni Clinical Institute, Bucharest, Romania
| | - C Gheorghe
- Fundeni Clinical Institute, Bucharest, Romania
| | - G E Theodoropoulos
- First Propaedeutic Surgical Department, "Hippocratio" General Hospital Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - F Bergmann
- Pathologisches Institut der Universität Heidelberg, Heidelberg, Germany
| | - H Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - L Vodickova
- Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic
| | - V Katzke
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - D Campa
- Dipartimento di Biologia, Università di Pisa, Pisa, Italy
| | - O Strobel
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Germany
| | - J Kaiser
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Germany
| | - R Pezzilli
- Pancreas Unit, Department of Digestive System, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - F Federici
- Department of Massa Carrara Oncological, Azienda USL Toscana Nord Ovest, Carrara, Italy
| | - B Mohelnikova-Duchonova
- Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - U Boggi
- Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy
| | - R Lemstrova
- Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - J S Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - S E Bojesen
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - I Chen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - B V Jensen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - G Capurso
- Digestive and Liver Disease Unit, Pancreatic Disorders Clinic, S. Andrea Hospital, University of Sapienza, Rome, Italy
- Pancreatico/Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - V Pazienza
- Division of Gastroenterology and Research Laboratory, Department of Oncology, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - C Dervenis
- Department of Surgery, Konstantopouleion General Hospital of Athens, Athens, Greece
| | - C Sperti
- Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Padova, Italy
| | - A Mambrini
- Department of Massa Carrara Oncological, Azienda USL Toscana Nord Ovest, Carrara, Italy
| | - T Hackert
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Germany
| | - R Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - D Basso
- Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy
| | - R Talar-Wojnarowska
- Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | - E Maiello
- Division of Gastroenterology and Research Laboratory, Department of Oncology, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - J R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - K Cuk
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - K U Saum
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - M Cantore
- Department of Massa Carrara Oncological, Azienda USL Toscana Nord Ovest, Carrara, Italy
| | - J Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - O Palmieri
- Division of Gastroenterology and Research Laboratory, Department of Oncology, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - G Delle Fave
- Digestive and Liver Disease Unit, Pancreatic Disorders Clinic, S. Andrea Hospital, University of Sapienza, Rome, Italy
| | - S Landi
- Dipartimento di Biologia, Università di Pisa, Pisa, Italy
| | - R Salvia
- Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
| | - P Fogar
- Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy
| | - Y K Vashist
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Section for Visceral Surgery, Department of Surgery, Kantonsspital Aarau AG, Aarau, Switzerland
| | - A Scarpa
- ARC-Net, Applied Research on Cancer Centre, University of Verona, Verona, Italy
| | - P Vodicka
- Institute of Experimental Medicine, Czech Academy of Science, Prague and Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic
| | - C Tjaden
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Germany
| | | | - F Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| |
Collapse
|
|
21
|
Corrias G, Raeside MC, Agostini A, Huicochea-Castellanos S, Aramburu-Nunez D, Paudyal R, Shukla-Dave A, Smelianskaia O, Capanu M, Zheng J, Fung M, Kelsen DP, Mangino DA, Robson ME, Goldfrank DJ, Carter J, Allen PJ, Conti B, Monti S, Do RKG, Mannelli L. Pilot study of rapid MR pancreas screening for patients with BRCA mutation. Eur Radiol 2019; 29:3976-3985. [PMID: 30689033 PMCID: PMC6609466 DOI: 10.1007/s00330-018-5975-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 10/16/2018] [Accepted: 12/14/2018] [Indexed: 01/03/2023]
Abstract
PURPOSE To develop and optimize a rapid magnetic resonance imaging (MRI) screening protocol for pancreatic cancer to be performed in conjunction with breast MRI screening in breast cancer susceptibility gene (BRCA)-positive individuals. METHODS An IRB-approved prospective study was conducted. The rapid screening pancreatic MR protocol was designed to be less than 10 min to be performed after a standard breast MRI protocol. Protocol consisted of coronal NT T2 SSFSE, axial NT T2 SSFSE and axial NT rFOV FOCUS DWI, and axial T1. Images were acquired with the patient in the same prone position of breast MRI using the built-in body coil. Image quality was qualitatively assessed by two radiologists with 12 and 13 years of MRI experience, respectively. The imaging protocol was modified until an endpoint of five consecutive patients with high-quality diagnostic images were achieved. Signal-to-noise ratio and contrast-to-noise ratio were assessed. RESULTS The rapid pancreas MR protocol was successfully completed in all patients. Diagnostic image quality was achieved for all patients. Excellent image quality was achieved for low b values; however, image quality at higher b values was more variable. In one patient, a pancreatic neuroendocrine tumor was found and the patient was treated surgically. In four patients, small pancreatic cystic lesions were detected. In one subject, a hepatic mass was identified and confirmed as adenoma by liver MRI. CONCLUSION Rapid MR protocol for pancreatic cancer screening is feasible and has the potential to play a role in screening BRCA patients undergoing breast MRI. KEY POINT • Develop and optimize a rapid magnetic resonance imaging (MRI) screening protocol for pancreatic cancer to be performed in conjunction with breast MRI screening in BRCA mutation positive individuals.
Collapse
Affiliation(s)
- Giuseppe Corrias
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
- Department of Radiology, University of Cagliari, Cagliari, Italy
| | - Mitchell C Raeside
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Andrea Agostini
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
- Department of Radiology, Università Politecnica delle Marche, Ancona, Italy
| | | | - David Aramburu-Nunez
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ramesh Paudyal
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Amita Shukla-Dave
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Olga Smelianskaia
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Marinela Capanu
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Junting Zheng
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maggie Fung
- GE Healthcare, Global MR Applications and Workflow, New York, NY, USA
| | - David P Kelsen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Debra A Mangino
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mark E Robson
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Deborah J Goldfrank
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jean Carter
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Peter J Allen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Bettina Conti
- Policlinico Umberto I, Department of Radiology, Sapienza University of Rome, Rome, Italy
| | | | - Richard K G Do
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Lorenzo Mannelli
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
| |
Collapse
|
|
22
|
Gendoo DMA, Zon M, Sandhu V, Manem VSK, Ratanasirigulchai N, Chen GM, Waldron L, Haibe-Kains B. MetaGxData: Clinically Annotated Breast, Ovarian and Pancreatic Cancer Datasets and their Use in Generating a Multi-Cancer Gene Signature. Sci Rep 2019; 9:8770. [PMID: 31217513 PMCID: PMC6584731 DOI: 10.1038/s41598-019-45165-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 05/31/2019] [Indexed: 12/13/2022] Open
Abstract
A wealth of transcriptomic and clinical data on solid tumours are under-utilized due to unharmonized data storage and format. We have developed the MetaGxData package compendium, which includes manually-curated and standardized clinical, pathological, survival, and treatment metadata across breast, ovarian, and pancreatic cancer data. MetaGxData is the largest compendium of curated transcriptomic data for these cancer types to date, spanning 86 datasets and encompassing 15,249 samples. Open access to standardized metadata across cancer types promotes use of their transcriptomic and clinical data in a variety of cross-tumour analyses, including identification of common biomarkers, and assessing the validity of prognostic signatures. Here, we demonstrate that MetaGxData is a flexible framework that facilitates meta-analyses by using it to identify common prognostic genes in ovarian and breast cancer. Furthermore, we use the data compendium to create the first gene signature that is prognostic in a meta-analysis across 3 cancer types. These findings demonstrate the potential of MetaGxData to serve as an important resource in oncology research, and provide a foundation for future development of cancer-specific compendia.
Collapse
Affiliation(s)
- Deena M A Gendoo
- Centre for Computational Biology, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
| | - Michael Zon
- Princess Margaret Cancer Center, University Health Network, Toronto, M5G 2C1, Canada.,Department of Biomedical Engineering, McMaster University, Toronto, L8S 4L8, Canada
| | - Vandana Sandhu
- Princess Margaret Cancer Center, University Health Network, Toronto, M5G 2C1, Canada
| | - Venkata S K Manem
- Princess Margaret Cancer Center, University Health Network, Toronto, M5G 2C1, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, M5S 3H7, Canada.,Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec City, G1V 4G5, Canada
| | | | - Gregory M Chen
- Princess Margaret Cancer Center, University Health Network, Toronto, M5G 2C1, Canada
| | - Levi Waldron
- Graduate School of Public Health and Health Policy, Institute of Implementation Science in Population Health, City University of New York School, New York, 11101, USA.
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Center, University Health Network, Toronto, M5G 2C1, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, M5S 3H7, Canada. .,Department of Computer Science, University of Toronto, Toronto, M5T 3A1, Canada. .,Ontario Institute of Cancer Research, Toronto, M5G 0A3, Canada. .,Vector Institute, Toronto, M5G 1M1, Canada.
| |
Collapse
|
|
23
|
Navarro EB, López EV, Quijano Y, Caruso R, Ferri V, Durand H, Cabrera IF, Reques ED, Ielpo B, Glagolieva AY, Plaza C. Impact of BRCA1/2 gene mutations on survival of patients with pancreatic cancer: A case-series analysis. Ann Hepatobiliary Pancreat Surg 2019; 23:200-205. [PMID: 31225426 PMCID: PMC6558134 DOI: 10.14701/ahbps.2019.23.2.200] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 12/10/2018] [Accepted: 12/14/2018] [Indexed: 12/19/2022] Open
Abstract
BRCA gene mutations are found in up to 10% of pancreatic adenocarcinoma cases. We present a description of 4 cases along with a review of the current literature regarding pathogenesis, target treatment, response and survival rates in these types of malignancies. We describe four cases of pancreatic adenocarcinoma, in three of which the BRCA2 mutation was identified, in one - BRCA1 gene alteration. Two patients underwent surgery following the neoadjuvant treatment with Folfirinox and radiotherapy; in the first case, a distal pancreatectomy with splenectomy was performed and in the second one - the Whipple's procedure. In both cases, a complete pathological response was reported. Other 2 patients were treated with Folfirinox after BRCA mutation identification and acceptable life expectancy was obtained. The association of pathologic complete response (PCR) with lower rates of local recurrence and better survival in patients with various types of adenocarcinomas is well known. Identification of such patients carrying BRCA mutations could provide an application of better personalized treatment. In some patients with pancreatic cancer, especially when there is clinical or demographic reason to suspect a genetic predisposition, a confirmation of the presence of BRCA mutations could provide an opportunity to use target treatment with beneficial outcomes regarding survival.
Collapse
Affiliation(s)
- Ernesto Barzola Navarro
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Emilio Vicente López
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Yolanda Quijano
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Riccardo Caruso
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Valentina Ferri
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Hipolito Durand
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Isabel Fabra Cabrera
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Eduardo Diaz Reques
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | - Benedetto Ielpo
- Department of General and Digestive Surgery, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | | | - Carlos Plaza
- Department of Pathology, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| |
Collapse
|
|
24
|
Jachimowicz RD, Goergens J, Reinhardt HC. DNA double-strand break repair pathway choice - from basic biology to clinical exploitation. Cell Cycle 2019; 18:1423-1434. [PMID: 31116084 DOI: 10.1080/15384101.2019.1618542] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Mutations in genes encoding components of the DNA damage response (DDR) are among the most frequent aberrations in human tumors. Moreover, a large array of human syndromes is caused by mutations in genes involved in DDR pathways. Among others, homologous recombination repair (HR) of DNA double-strand breaks (DSB) is frequently affected by disabling mutations. While impaired HR is clearly promoting tumorigenesis, it is also associated with an actionable sensitivity against PARP inhibitors. PARP inhibitors have recently received FDA approval for the treatment of breast- and ovarian cancer. However, as with all molecularly targeted agents, acquired resistance limits its use. Both pharmaco-genomic approaches and the study of human genome instability syndromes have led to a profound understanding of PARP inhibitor resistance. These experiments have revealed new insights into the molecular mechanisms that drive mammalian DSB repair. Here, we review recent discoveries in the field and provide a clinical perspective.
Collapse
Affiliation(s)
- Ron D Jachimowicz
- a Clinic I of Internal Medicine , University Hospital Cologne , Cologne , Germany
| | - Jonas Goergens
- a Clinic I of Internal Medicine , University Hospital Cologne , Cologne , Germany
| | - H Christian Reinhardt
- a Clinic I of Internal Medicine , University Hospital Cologne , Cologne , Germany.,b Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases , University of Cologne , Cologne , Germany.,c Center for Molecular Medicine Cologne , University of Cologne , Cologne , Germany.,d Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf, Cologne Site , University of Cologne , Cologne , Germany
| |
Collapse
|
|
25
|
Kryklyva V, Haj Mohammad N, Morsink FHM, Ligtenberg MJL, Offerhaus GJA, Nagtegaal ID, de Leng WWJ, Brosens LAA. Pancreatic acinar cell carcinoma is associated with BRCA2 germline mutations: a case report and literature review. Cancer Biol Ther 2019; 20:949-955. [PMID: 31002019 PMCID: PMC6606020 DOI: 10.1080/15384047.2019.1595274] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Acinar cell carcinoma (ACC) is a rare pancreatic neoplasm with dismal prognosis. Insights into the molecular basis of ACC can pave the way for the application of more effective, personalized therapies and detection of patients with hereditary predisposition. Molecular analysis revealed a germline BRCA2 (and CHEK2) mutation in a patient with a rare pancreatic ACC with extensive intraductal growth. Somatic loss of the wild-type BRCA2 allele in the tumor indicated the causal relationship of ACC with the germline defect. A thorough literature review identified another nine ACCs associated with germline BRCA2 mutation and two ACCs associated with germline BRCA1 mutation, resulting in a prevalence of BRCA1/2 germline mutations in almost 7% of ACCs. Moreover, somatic BRCA1/2 alterations are reported in 16% of sporadic ACCs. Overall, about one fifth (22%) of all pancreatic ACCs exhibit BRCA1/2 deficiency. This study underscores the important role of BRCA1/2 mutations in pancreatic ACC. All ACC patients should undergo genetic testing for BRCA1/2 mutations to identify carriers of pathogenic variants. This will allow to select patients that can benefit from targeted therapies directed against BRCA1/2-deficient tumors and is also crucial as a referral to genetic screening for the relatives of affected individuals carrying germline BRCA1/2 alterations. Abbreviations: ACC: acinar cell carcinoma; HBOC: Hereditary Breast and Ovarian Cancer; LOH: loss of heterozygosity; PARP: poly (ADP-ribose) polymerase; PDAC: pancreatic ductal adenocarcinoma; PP: pancreatic panniculitis; SD: standard deviation; WES: whole-exome sequencing.
Collapse
Affiliation(s)
- Valentyna Kryklyva
- a Department of Pathology , Radboud Institute for Molecular Life Sciences, Radboud university medical center , Nijmegen , The Netherlands
| | - Nadia Haj Mohammad
- b Department of Medical Oncology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - Folkert H M Morsink
- c Department of Pathology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - Marjolijn J L Ligtenberg
- a Department of Pathology , Radboud Institute for Molecular Life Sciences, Radboud university medical center , Nijmegen , The Netherlands.,d Department of Human Genetics , Radboud Institute for Molecular Life Sciences, Radboud university medical center , Nijmegen , The Netherlands
| | - G Johan A Offerhaus
- c Department of Pathology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - Iris D Nagtegaal
- a Department of Pathology , Radboud Institute for Molecular Life Sciences, Radboud university medical center , Nijmegen , The Netherlands
| | - Wendy W J de Leng
- c Department of Pathology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| | - Lodewijk A A Brosens
- a Department of Pathology , Radboud Institute for Molecular Life Sciences, Radboud university medical center , Nijmegen , The Netherlands.,c Department of Pathology , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands
| |
Collapse
|
|
26
|
Cervantes A, Waymouth EK, Petrov MS. African-Americans and Indigenous Peoples Have Increased Burden of Diseases of the Exocrine Pancreas: A Systematic Review and Meta-Analysis. Dig Dis Sci 2019; 64:249-261. [PMID: 30259278 DOI: 10.1007/s10620-018-5291-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 09/14/2018] [Indexed: 12/12/2022]
Abstract
Ethnic health disparity is a well-acknowledged issue in many disease settings, but not diseases of the exocrine pancreas. A systematic review and meta-analysis was conducted to explore the race- and ethnicity-specific burden of diseases of the exocrine pancreas. Studies that compared health-related endpoints between two or more ethnicities were eligible for inclusion. Proportion meta-analyses were conducted to compare burden between groups. A total of 42 studies (24 on pancreatic cancer, 17 on pancreatitis, and one on pancreatic cyst) were included in the systematic review, of which 19 studies were suitable for meta-analyses. The incidence of pancreatic cancer was 1.4-fold higher among African-Americans, while the incidence of acute pancreatitis was 4.8-fold higher among an indigenous population (New Zealand Māori) compared with Caucasians. The prevalence of post-pancreatitis diabetes mellitus was up to 3.0-fold higher among certain ethnicities, including Asians, Pacific Islanders, and indigenous populations compared with Caucasians. The burden of diseases of the exocrine pancreas differs between ethnicities, with African-Americans and certain indigenous populations being at the greatest risk of developing these diseases. Development of race- and ethnicity-specific screening as well as protocols for lifestyle modifications may need to be considered with a view to reducing the disparities in burden of diseases of the exocrine pancreas.
Collapse
Affiliation(s)
- Aya Cervantes
- School of Medicine, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Ellen K Waymouth
- School of Medicine, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Maxim S Petrov
- School of Medicine, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
| |
Collapse
|
|
27
|
Parkin A, Man J, Chou A, Nagrial AM, Samra J, Gill AJ, Timpson P, Pajic M. The Evolving Understanding of the Molecular and Therapeutic Landscape of Pancreatic Ductal Adenocarcinoma. Diseases 2018; 6:diseases6040103. [PMID: 30428574 PMCID: PMC6313363 DOI: 10.3390/diseases6040103] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 11/07/2018] [Accepted: 11/08/2018] [Indexed: 12/18/2022] Open
Abstract
Pancreatic cancer is the third leading cause of cancer-related deaths, characterised by poor survival, marked molecular heterogeneity and high intrinsic and acquired chemoresistance. Only 10⁻20% of pancreatic cancer patients present with surgically resectable disease and even then, 80% die within 5 years. Our increasing understanding of the genomic heterogeneity of cancer suggests that the failure of definitive clinical trials to demonstrate efficacy in the majority of cases is likely due to the low proportion of responsive molecular subtypes. As a consequence, novel treatment strategies to approach this disease are urgently needed. Significant developments in the field of precision oncology have led to increasing molecular stratification of cancers into subtypes, where individual cancers are selected for optimal therapy depending on their molecular or genomic fingerprint. This review provides an overview of the current status of clinically used and emerging treatment strategies, and discusses the advances in and the potential for the implementation of precision medicine in this highly lethal malignancy, for which there are currently no curative systemic therapies.
Collapse
Affiliation(s)
- Ashleigh Parkin
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
| | - Jennifer Man
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
| | - Angela Chou
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
- University of Sydney, Sydney, NSW 2006, Australia.
| | - Adnan M Nagrial
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
- Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW 2145, Australia.
| | - Jaswinder Samra
- Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia.
| | - Anthony J Gill
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
- University of Sydney, Sydney, NSW 2006, Australia.
- Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia.
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia.
| | - Paul Timpson
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
- St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia.
| | - Marina Pajic
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
- St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia.
| |
Collapse
|
|
28
|
Schmitt A, Feldmann G, Zander T, Reinhardt HC. Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma. Oncol Res Treat 2018; 41:619-625. [DOI: 10.1159/000493401] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 08/31/2018] [Indexed: 12/12/2022]
|
|
29
|
Zhu Y, Zhai K, Ke J, Li J, Gong Y, Yang Y, Tian J, Zhang Y, Zou D, Peng X, Gong J, Zhong R, Huang K, Chang J, Miao X. BRCA1 missense polymorphisms are associated with poor prognosis of pancreatic cancer patients in a Chinese population. Oncotarget 2018; 8:36033-36039. [PMID: 28415599 PMCID: PMC5482636 DOI: 10.18632/oncotarget.16422] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 03/15/2017] [Indexed: 01/24/2023] Open
Abstract
Pancreatic cancer is a highly lethal disease with limited prognostic marker. BRAC1 and BRCA2 are two classic tumor suppressor genes which play an important role in DNA repair. Somatic mutations and germline genetic variants on BRCA1/2 have been found associated with the tumorigenesis of pancreatic cancer. However, the correlations between BRCA1/2 polymorphism and pancreatic cancer prognosis remained unknown. In this study, we genotyped three tag missense variants on BRCA1/2 in 603 sporadic pancreatic cancer patients in a Chinese population. We found rs1799966 on BRCA1 was associated with poor prognosis of pancreatic cancer patients with hazard ratio being 1.23 (95% CI: 1.09–1.40, P = 0.0010). Further stratification analyses showed that significant correlation was particularly in locally advanced stage patients with hazard ratio being 1.36 (95% CI: 1.13–1.64, P = 0.0014), but not in patients in local stage (P = 0.1139) or metastatic stage (P = 0.5185). Two missense variants (rs766173 and rs144848) on BRAC2 showed no significant correlation with pancreatic cancer patients’ overall survival. In conclusion, we identified a germline missense variant on BRAC1 significantly associated with poor prognosis of pancreatic cancer patients with locally advanced stage. These results may contribute to the precision medicine of this disease.
Collapse
Affiliation(s)
- Ying Zhu
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kan Zhai
- Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Juntao Ke
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaoyuan Li
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yajie Gong
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Yang
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianbo Tian
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Zhang
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Danyi Zou
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiating Peng
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Gong
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rong Zhong
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Huang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China
| | - Jiang Chang
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Miao
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
30
|
A Contemporary Review of the Treatment Landscape and the Role of Predictive and Prognostic Biomarkers in Pancreatic Adenocarcinoma. Can J Gastroenterol Hepatol 2018; 2018:1863535. [PMID: 29623263 PMCID: PMC5829312 DOI: 10.1155/2018/1863535] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 01/17/2018] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer continues to represent one of the leading causes of cancer-related morbidity and mortality in the developed world. Over the past decade, novel systemic therapy combination regimens have contributed to clinically meaningful and statistically significant improvements in overall survival as compared to conventional monotherapy. However, the prognosis for most patients remains guarded secondary to the advanced stages of disease at presentation. There is growing consensus that outcomes can be further optimized with the use of predictive and prognostic biomarkers whereby the former can be enriching for patients who would benefit from therapies and the latter can inform decision-making regarding the need and timing of advanced care planning. One of the challenges of current biomarkers is the lack of standardization across clinical practices such that comparability between jurisdictions can be difficult or even impossible. This inconsistency can impede widespread implementation of their use. In this review article, we provide a comprehensive overview of the contemporary treatment options for pancreatic cancer and we offer some insights into the existing landscape and future directions of biomarker development for this disease.
Collapse
|
|
31
|
Digennaro M, Sambiasi D, Tommasi S, Pilato B, Diotaiuti S, Kardhashi A, Trojano G, Tufaro A, Paradiso AV. Hereditary and non-hereditary branches of family eligible for BRCA test: cancers in other sites. Hered Cancer Clin Pract 2017; 15:7. [PMID: 28559958 PMCID: PMC5445420 DOI: 10.1186/s13053-017-0067-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 05/17/2017] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The analysis of relationships of BRCA alterations with cancer at sites other than breast/ovary may provide innovative information concerning BRCA pathogenic role and support additional clinical decisions. Aim of this study is to compare presence of cancers in other sites in members of hereditary (H) and not-hereditary (nH) branches of families of patients eligible to BRCA test. METHODS We retrospectively analyzed the incidence of cancer in other sites in members of 136 families eligible for hereditary breast/ovarian cancer genetic counseling at Centro Studi Tumori Eredo-familiari of our Institute; we compared the frequency of other cancer types in 1156 members of the H-branch with respect to 1062 members of nH-Branch. The families belonging to a proband case and with informative members in at least three generation entered the present study. RESULTS The frequency of other Cancers in members of H-branch was significantly higher than that in members of nH-branch (161 vs 75 cancers; p < 0.0001). In specific, members of H-branch had a significantly higher probability to have more lung cancer (38 vs 9;p < 0.0006), kidney cancer (23 vs 5;p < 0.0005), liver cancer (13 vs 3;p < 0.02) and larynx cancer (14 vs 4;p < 0.03). Interestingly, to belong to H-branch resulted significantly associated with a higher probability of lung cancer (OR 4.5; 2.15-9.38 95%C.I.), liver cancer (OR: 4.02; 1.14-14.15 95% C.I.) and larynx cancer (OR:3.4; 1.12-10.39 95%C.I.) independently from Gender and Age. CONCLUSIONS Members belonging to the H-branch of families of patients eligible to BRCA test have a higher risk of tumors in lung, larynx and liver. Clinicians should consider the increased risk for these cancers to activate prevention/early diagnosis practices in members of families with breast/ovarian familial cancer syndrome.
Collapse
Affiliation(s)
- M Digennaro
- Centro Studi Tumori Eredo-familiari. Istituto Tumori G Paolo II,IRCCS, 70124 Bari, Italy
| | - D Sambiasi
- Centro Studi Tumori Eredo-familiari. Istituto Tumori G Paolo II,IRCCS, 70124 Bari, Italy
| | - S Tommasi
- Laboratorio Genetica Molecolare; Istituto Tumori G Paolo II, IRCCS, 70124 Bari, Italy
| | - B Pilato
- Laboratorio Genetica Molecolare; Istituto Tumori G Paolo II, IRCCS, 70124 Bari, Italy
| | - S Diotaiuti
- UO Senologia Tumori. Istituto Tumori G Paolo II,IRCCS, 70124 Bari, Italy
| | - A Kardhashi
- UO Senologia Tumori. Istituto Tumori G Paolo II,IRCCS, 70124 Bari, Italy.,UO Ginecologia Oncologica, Istituto Tumori G Paolo II, IRCCS, 70124 Bari, Italy
| | - G Trojano
- ASST Fatebene Fratelli, Milan, Italy
| | - A Tufaro
- Biobanca Istituzionale, Istituto Tumori G Paolo II, IRCCS, 70124 Bari, Italy
| | - A V Paradiso
- Centro Studi Tumori Eredo-familiari. Istituto Tumori G Paolo II,IRCCS, 70124 Bari, Italy.,Centro Studi Tumori Eredo-Familiari, Istituto Tumori G Paolo II, IRCCS, Via O. Flacco, 65, 70124 Bari, Italy
| |
Collapse
|
|
32
|
Khan MAA, Azim S, Zubair H, Bhardwaj A, Patel GK, Khushman M, Singh S, Singh AP. Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward. Int J Mol Sci 2017; 18:ijms18040779. [PMID: 28383487 PMCID: PMC5412363 DOI: 10.3390/ijms18040779] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 03/28/2017] [Accepted: 03/30/2017] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.
Collapse
Affiliation(s)
- Mohammad Aslam Aslam Khan
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Shafquat Azim
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Haseeb Zubair
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Arun Bhardwaj
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Girijesh Kumar Patel
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Moh'd Khushman
- Departments of Interdisciplinary Clinical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Seema Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
| | - Ajay Pratap Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
| |
Collapse
|
|
33
|
Trescher S, Münchmeyer J, Leser U. Estimating genome-wide regulatory activity from multi-omics data sets using mathematical optimization. BMC SYSTEMS BIOLOGY 2017; 11:41. [PMID: 28347313 PMCID: PMC5369021 DOI: 10.1186/s12918-017-0419-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 03/08/2017] [Indexed: 12/28/2022]
Abstract
Background Gene regulation is one of the most important cellular processes, indispensable for the adaptability of organisms and closely interlinked with several classes of pathogenesis and their progression. Elucidation of regulatory mechanisms can be approached by a multitude of experimental methods, yet integration of the resulting heterogeneous, large, and noisy data sets into comprehensive and tissue or disease-specific cellular models requires rigorous computational methods. Recently, several algorithms have been proposed which model genome-wide gene regulation as sets of (linear) equations over the activity and relationships of transcription factors, genes and other factors. Subsequent optimization finds those parameters that minimize the divergence of predicted and measured expression intensities. In various settings, these methods produced promising results in terms of estimating transcription factor activity and identifying key biomarkers for specific phenotypes. However, despite their common root in mathematical optimization, they vastly differ in the types of experimental data being integrated, the background knowledge necessary for their application, the granularity of their regulatory model, the concrete paradigm used for solving the optimization problem and the data sets used for evaluation. Results Here, we review five recent methods of this class in detail and compare them with respect to several key properties. Furthermore, we quantitatively compare the results of four of the presented methods based on publicly available data sets. Conclusions The results show that all methods seem to find biologically relevant information. However, we also observe that the mutual result overlaps are very low, which contradicts biological intuition. Our aim is to raise further awareness of the power of these methods, yet also to identify common shortcomings and necessary extensions enabling focused research on the critical points. Electronic supplementary material The online version of this article (doi:10.1186/s12918-017-0419-z) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Saskia Trescher
- Knowledge Management in Bioinformatics, Computer Science Department, Humboldt-Universität zu Berlin, Unter den Linden 6, 10099, Berlin, Germany.
| | - Jannes Münchmeyer
- Knowledge Management in Bioinformatics, Computer Science Department, Humboldt-Universität zu Berlin, Unter den Linden 6, 10099, Berlin, Germany
| | - Ulf Leser
- Knowledge Management in Bioinformatics, Computer Science Department, Humboldt-Universität zu Berlin, Unter den Linden 6, 10099, Berlin, Germany
| |
Collapse
|
|
34
|
McCubrey JA, Rakus D, Gizak A, Steelman LS, Abrams SL, Lertpiriyapong K, Fitzgerald TL, Yang LV, Montalto G, Cervello M, Libra M, Nicoletti F, Scalisi A, Torino F, Fenga C, Neri LM, Marmiroli S, Cocco L, Martelli AM. Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity-Diverse effects on cell growth, metabolism and cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:2942-2976. [PMID: 27612668 DOI: 10.1016/j.bbamcr.2016.09.004] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 08/14/2016] [Accepted: 09/02/2016] [Indexed: 02/07/2023]
Abstract
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Wnt/beta-catenin, hedgehog, Notch and TP53. Mutations that occur in these and other pathways can alter the effects that natural GSK-3 activity has on regulating these signaling circuits that can lead to cancer as well as other diseases. The novel roles that microRNAs play in regulation of the effects of GSK-3 will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance.
Collapse
Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA.
| | - Dariusz Rakus
- Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland
| | - Agnieszka Gizak
- Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA
| | - Steve L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine at East Carolina University, USA
| | - Timothy L Fitzgerald
- Department of Surgery, Brody School of Medicine at East Carolina University, USA
| | - Li V Yang
- Department of Internal Medicine, Hematology/Oncology Section, Brody School of Medicine at East Carolina University, USA
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy; Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Melchiorre Cervello
- Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Massimo Libra
- Department of Bio-medical Sciences, University of Catania, Catania, Italy
| | | | - Aurora Scalisi
- Unit of Oncologic Diseases, ASP-Catania, Catania 95100, Italy
| | - Francesco Torino
- Department of Systems Medicine, Chair of Medical Oncology, Tor Vergata University of Rome, Rome, Italy
| | - Concettina Fenga
- Department of Biomedical, Odontoiatric, Morphological and Functional Images, Occupational Medicine Section - Policlinico "G. Martino" - University of Messina, Messina 98125, Italy
| | - Luca M Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Sandra Marmiroli
- Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy
| | - Lucio Cocco
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Alberto M Martelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| |
Collapse
|
|
35
|
Kourie HR, Gharios J, Elkarak F, Antoun J, Ghosn M. Is metastatic pancreatic cancer an untargetable malignancy? World J Gastrointest Oncol 2016; 8:297-304. [PMID: 26989465 PMCID: PMC4789615 DOI: 10.4251/wjgo.v8.i3.297] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 11/09/2015] [Accepted: 12/21/2015] [Indexed: 02/05/2023] Open
Abstract
Metastatic pancreatic cancer (MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies (TT). Erlotinib combined to gemcitabine is the only targeted therapy that showed an overall survival benefit in MPC. New targets and therapeutic approaches, based on new-TT, are actually being evaluated in MPC going from immunotherapy, epigenetics, tumor suppressor gene and oncogenes to stromal matrix regulators. We aim in this paper to present the major causes rendering MPC an untargetable malignancy and to focus on the new therapeutic modalities based on TT in MPC.
Collapse
|
|
36
|
Samadder P, Aithal R, Belan O, Krejci L. Cancer TARGETases: DSB repair as a pharmacological target. Pharmacol Ther 2016; 161:111-131. [PMID: 26899499 DOI: 10.1016/j.pharmthera.2016.02.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cancer is a disease attributed to the accumulation of DNA damages due to incapacitation of DNA repair pathways resulting in genomic instability and a mutator phenotype. Among the DNA lesions, double stranded breaks (DSBs) are the most toxic forms of DNA damage which may arise as a result of extrinsic DNA damaging agents or intrinsic replication stress in fast proliferating cancer cells. Accurate repair of DSBs is therefore paramount to the cell survival, and several classes of proteins such as kinases, nucleases, helicases or core recombinational proteins have pre-defined jobs in precise execution of DSB repair pathways. On one hand, the proper functioning of these proteins ensures maintenance of genomic stability in normal cells, and on the other hand results in resistance to various drugs employed in cancer therapy and therefore presents a suitable opportunity for therapeutic targeting. Higher relapse and resistance in cancer patients due to non-specific, cytotoxic therapies is an alarming situation and it is becoming more evident to employ personalized treatment based on the genetic landscape of the cancer cells. For the success of personalized treatment, it is of immense importance to identify more suitable targetable proteins in DSB repair pathways and also to explore new synthetic lethal interactions with these pathways. Here we review the various alternative approaches to target the various protein classes termed as cancer TARGETases in DSB repair pathway to obtain more beneficial and selective therapy.
Collapse
Affiliation(s)
- Pounami Samadder
- National Centre for Biomolecular Research, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, 60200 Brno, Czech Republic
| | - Rakesh Aithal
- National Centre for Biomolecular Research, Masaryk University, 62500 Brno, Czech Republic; Department of Biology, Masaryk University, 62500 Brno, Czech Republic
| | - Ondrej Belan
- Department of Biology, Masaryk University, 62500 Brno, Czech Republic
| | - Lumir Krejci
- National Centre for Biomolecular Research, Masaryk University, 62500 Brno, Czech Republic; International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, 60200 Brno, Czech Republic; Department of Biology, Masaryk University, 62500 Brno, Czech Republic.
| |
Collapse
|
|
37
|
Alexandrov LB, Nik-Zainal S, Siu HC, Leung SY, Stratton MR. A mutational signature in gastric cancer suggests therapeutic strategies. Nat Commun 2015; 6:8683. [PMID: 26511885 PMCID: PMC4918743 DOI: 10.1038/ncomms9683] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 09/18/2015] [Indexed: 12/17/2022] Open
Abstract
Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum therapy exhibit this mutational signature including a sample that lacked any defects in BRCA1 or BRCA2. Here, we examine 10,250 cancer genomes across 36 types of cancer and demonstrate that, in addition to breast, ovarian and pancreatic cancers, gastric cancer is another cancer type that exhibits this mutational signature. Our results suggest that 7–12% of gastric cancers have defective double-strand DNA break repair by homologous recombination and may benefit from either platinum therapy or PARP inhibitors. Cancer genome analysis has demonstrated that some breast and ovarian tumours show reduced homologous recombination, a feature that can be therapeutically exploited. Here, Alexandrov et al. search for this mutational signature in 36 different cancer types and find that some gastric tumours also harbour this mutational spectrum.
Collapse
Affiliation(s)
- Ludmil B Alexandrov
- Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.,Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.,Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA
| | - Serena Nik-Zainal
- Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.,Department of Medical Genetics, Addenbrooke's Hospital National Health Service (NHS) Trust, Cambridge CB2 0QQ, UK
| | - Hoi Cheong Siu
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Suet Yi Leung
- Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Michael R Stratton
- Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
| |
Collapse
|
|
38
|
Luo G, Lu Y, Jin K, Cheng H, Guo M, Liu Z, Long J, Liu C, Ni Q, Yu X. Pancreatic cancer: BRCA mutation and personalized treatment. Expert Rev Anticancer Ther 2015; 15:1223-1231. [PMID: 26402249 DOI: 10.1586/14737140.2015.1086271] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The highly heterozygous nature of pancreatic cancer is partially responsible for its therapeutic ineffectiveness and resistance. Therefore, the ability to identify subgroups of pancreatic cancer with unique biological characteristics and treatment response is urgently needed. In addition to breast and ovarian cancer, pancreatic cancer is the third most common cancer type that is related to the early onset (BRCA) gene mutation in breast cancer. Mounting evidence has demonstrated that BRCA1/2-mutant breast and ovarian cancers are highly sensitive to DNA damage-related treatment, including poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum-based agents. Preliminary evidence also showed promising results for DNA damage-related treatment in BRCA1/2-mutant pancreatic cancer. Importantly, several prospective clinical trials of PARPi-based regimens are underway for BRCA1/2-mutated pancreatic cancer. Pancreatic cancer with a BRCA1/2 mutation is a small subgroup with a promising therapeutic strategy.
Collapse
|
|
39
|
Bai G, Wu C, Gao Y, Shu G. Exploring the Functional Disorder and Corresponding Key Transcription Factors in Intraductal Papillary Mucinous Neoplasms Progression. Int J Genomics 2015; 2015:197603. [PMID: 26425543 PMCID: PMC4573622 DOI: 10.1155/2015/197603] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 08/11/2015] [Indexed: 12/18/2022] Open
Abstract
This study has analyzed the gene expression patterns of an IPMN microarray dataset including normal pancreatic ductal tissue (NT), intraductal papillary mucinous adenoma (IPMA), intraductal papillary mucinous carcinoma (IPMC), and invasive ductal carcinoma (IDC) samples. And eight clusters of differentially expressed genes (DEGs) with similar expression pattern were detected by k-means clustering. Then a survey map of functional disorder in IPMN progression was established by functional enrichment analysis of these clusters. In addition, transcription factors (TFs) enrichment analysis was used to detect the key TFs in each cluster of DEGs, and three TFs (FLI1, ERG, and ESR1) were found to significantly regulate DEGs in cluster 1, and expression of these three TFs was validated by qRT-PCR. All these results indicated that these three TFs might play key roles in the early stages of IPMN progression.
Collapse
Affiliation(s)
- Guiying Bai
- Department of Oncology, Tianjin Third Central Hospital, Tianjin 300179, China
- Key Laboratory of Artificial Cell Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin 300179, China
| | - Chenxuan Wu
- Department of Oncology, Tianjin Third Central Hospital, Tianjin 300179, China
| | - Yingtang Gao
- Key Laboratory of Artificial Cell Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin 300179, China
| | - Guiming Shu
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin 300179, China
| |
Collapse
|
|
40
|
Cavanagh H, Rogers KMA. The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers. Hered Cancer Clin Pract 2015; 13:16. [PMID: 26236408 PMCID: PMC4521499 DOI: 10.1186/s13053-015-0038-x] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 07/28/2015] [Indexed: 02/07/2023] Open
Abstract
The association of germline mutations in the breast cancer susceptibility gene 1 (BRCA1) and the breast cancer susceptibility gene 2 (BRCA2) with the development of breast and ovarian cancers have been widely researched and recognised. It is known that these genes function at multiple sites in the body. Research has subsequently evolved into the connection of BRCA1/2 with cancers at other sites within the body. This review examines the association of BRCA1/2 germline gene mutations with prostate, pancreatic and stomach cancers. An extensive literature search revealed conflicting findings regarding the association of BRCA1/2 gene mutations with these cancers. Most studies suggest that there is an association between BRCA1/2 mutations and carcinoma of the prostate, pancreas and stomach, but some reports propose that such a correlation may be due to factors other than possessing a mutated BRCA1/2 gene, and other associations may be revealed as further epidemiological information becomes available. The review concludes that as more knowledge arises about the mechanisms of BRCA1/2 gene mutations, it should pave the way for future screening programmes to be applied effectively.
Collapse
Affiliation(s)
- Helen Cavanagh
- School of Nursing and Midwifery, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL N. Ireland
| | - Katherine M A Rogers
- School of Nursing and Midwifery, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL N. Ireland
| |
Collapse
|
|
41
|
Medina-Franco H, Pimienta-Ibarra AS, Pastor-Sifuentes FU, Ramírez-Luna MÁ. Simultaneous primary cancers: Atypical Lynch syndrome? REVISTA DE GASTROENTEROLOGIA DE MEXICO 2015; 80:169-170. [PMID: 25823775 DOI: 10.1016/j.rgmx.2014.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 11/27/2014] [Indexed: 06/04/2023]
Affiliation(s)
- H Medina-Franco
- Servicio de Cirugía Oncológica, Departamento de Cirugía, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México D.F, México.
| | - A S Pimienta-Ibarra
- Servicio de Cirugía Oncológica, Departamento de Cirugía, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México D.F, México
| | - F U Pastor-Sifuentes
- Servicio de Cirugía Oncológica, Departamento de Cirugía, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México D.F, México
| | - M Á Ramírez-Luna
- Departamento de Endoscopia, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México D.F, México
| |
Collapse
|
|
42
|
Medina-Franco H, Pimienta-Ibarra A, Pastor-Sifuentes F, Ramírez-Luna M. Simultaneous primary cancer: Atypical Lynch syndrome? REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2015. [DOI: 10.1016/j.rgmxen.2015.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
|
|
43
|
Chmielecki J, Hutchinson KE, Frampton GM, Chalmers ZR, Johnson A, Shi C, Elvin J, Ali SM, Ross JS, Basturk O, Balasubramanian S, Lipson D, Yelensky R, Pao W, Miller VA, Klimstra DS, Stephens PJ. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov 2014; 4:1398-405. [PMID: 25266736 DOI: 10.1158/2159-8290.cd-14-0617] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Pancreatic acinar cell carcinomas (PACC) account for approximately 1% (∼500 cases) of pancreatic cancer diagnoses annually in the United States. Oncogenic therapuetic targets have proven elusive in this disease, and chemotherapy and radiotherapy have demonstrated limited efficacy against these tumors. Comprehensive genomic profiling of a large series of PACCs (n=44) identified recurrent rearrangements involving BRAF and RAF1 (CRAF) in approximately 23% of tumors. The most prevalent fusion, SND1-BRAF, resulted in activation of the MAPK pathway, which was abrogated with MEK inhibition. SND1-BRAF-transformed cells were sensitive to treatment with the MEK inhibitor trametinib. PACCs lacking RAF rearrangements were significantly enriched for genomic alterations, causing inactivation of DNA repair genes (45%); these genomic alterations have been associated with sensitivity to platinum-based therapies and PARP inhibitors. Collectively, these results identify potentially actionable genomic alterations in the majority of PACCs and provide a rationale for using personalized therapies in this disease. SIGNIFICANCE PACC is genomically distinct from other pancreatic cancers. Fusions in RAF genes and mutually exclusive inactivation of DNA repair genes represent novel potential therapeutic targets that are altered in over two thirds of these tumors.
Collapse
Affiliation(s)
| | | | | | | | | | - Chanjuan Shi
- Vanderbilt University Medical Center, Nashville, Tennessee
| | - Julia Elvin
- Foundation Medicine, Cambridge, Massachusetts
| | - Siraj M Ali
- Foundation Medicine, Cambridge, Massachusetts
| | - Jeffrey S Ross
- Foundation Medicine, Cambridge, Massachusetts. Albany Medical College, Albany, New York
| | - Olca Basturk
- Memorial Sloan Kettering Cancer Center, New York, New York
| | | | | | | | - William Pao
- Vanderbilt University Medical Center, Nashville, Tennessee
| | | | | | | |
Collapse
|
|
44
|
Dietlein F, Reinhardt HC. Molecular Pathways: Exploiting Tumor-Specific Molecular Defects in DNA Repair Pathways for Precision Cancer Therapy. Clin Cancer Res 2014; 20:5882-7. [DOI: 10.1158/1078-0432.ccr-14-1165] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
|
|
45
|
Dietlein F, Thelen L, Reinhardt HC. Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches. Trends Genet 2014; 30:326-39. [PMID: 25017190 DOI: 10.1016/j.tig.2014.06.003] [Citation(s) in RCA: 204] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 06/12/2014] [Accepted: 06/18/2014] [Indexed: 12/13/2022]
Abstract
Defects in DNA repair pathways enable cancer cells to accumulate genomic alterations that contribute to their aggressive phenotype. However, tumors rely on residual DNA repair capacities to survive the damage induced by genotoxic stress. This dichotomy might explain why only isolated DNA repair pathways are inactivated in cancer cells. Accordingly, synergism has been observed between DNA-damaging drugs and targeted inhibitors of DNA repair. DNA repair pathways are generally thought of as mutually exclusive mechanistic units handling different types of lesions in distinct cell cycle phases. Recent preclinical studies, however, provide strong evidence that multifunctional DNA repair hubs, which are involved in multiple conventional DNA repair pathways, are frequently altered in cancer. We therefore propose that targeted anticancer therapies should not only exploit synthetic lethal interactions between two single genes but also consider alterations in DNA repair hubs. Such a network-based approach considerably increases the opportunities for targeting DNA repair-defective tumors.
Collapse
Affiliation(s)
- Felix Dietlein
- Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
| | - Lisa Thelen
- Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany
| | - H Christian Reinhardt
- Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
| |
Collapse
|
|
46
|
Squamous Cell Carcinoma of the Pancreas in a Patient with Germline BRCA2 Mutation-Response to Neoadjuvant Radiochemotherapy. Case Rep Oncol Med 2014; 2014:860532. [PMID: 24959366 PMCID: PMC4052146 DOI: 10.1155/2014/860532] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 05/07/2014] [Indexed: 11/17/2022] Open
Abstract
Primary squamous cell carcinoma of the pancreas is a rare malignant neoplasia, accounting for approximately 0.5–2% of all malignant pancreatic tumors. These lesions are characterized by poor prognosis. Here we report on a case of a 57-year-old female patient with known BRCA2 germline mutation presenting with primary squamous cell carcinoma of the pancreas as the only malignancy. The tumor was locally advanced at the first presentation but responded almost completely to neoadjuvant radio-chemotherapy. Our case highlights the facts (i) that pancreatic carcinomas belong to the tumor spectrum of patients with the BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) and (ii) that tumors of the pancreas can represent the first or even the only manifestation of HBOC. Furthermore, this case of a nonkeratinizing squamous cell carcinoma indicates that HBOC-associated carcinomas of the pancreas might be characterized by a broader morphological spectrum than was previously thought. Since BRCA mutations cause deficiency of DNA double-strand breakage repair in tumors, neoadjuvant treatment regimens might become a reasonable option in HBOC-associated pancreatic carcinomas. To our knowledge, this is the first reported case of a primary pancreatic squamous cell carcinoma in a patient with this particular genetic background of BRCA2-associated HBOC.
Collapse
|
|
47
|
Wang BS, Liu Z, Sun SL, Zhao Y. Identification of genes and candidate agents associated with pancreatic cancer. Tumour Biol 2013; 35:81-8. [PMID: 23934415 DOI: 10.1007/s13277-013-1009-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 07/08/2013] [Indexed: 10/26/2022] Open
Abstract
Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. A major challenge in current cancer research is biological interpretation of complexity of cancer somatic mutation profiles. It has been suggested that several molecular alterations may play important roles in pancreatic carcinogenesis. In this study, by using the GSE28735 affymetrix microarray data accessible from Gene Expression Omnibus (GEO) database, we identified differentially expressed genes (DEGs) between paired pancreatic cancer tissues and adjacent nontumor tissues, followed the protein-protein interaction of the DEGs. Our study identified thousands of DEGs involved in regulation of cell cycle and apoptosis in progression of pancreatic cancer. Sp1 was predicted to be the major regulator by transcription factors analysis. From the protein-protein interaction networks, we found that Tk1 might play an important role in the progression of pancreatic cancer. Finally, we predicted candidate agents, including tomatidine and nialamide, which may be used as drugs to treat pancreatic cancer. In conclusion, our data provide a comprehensive bioinformatics analysis of genes and pathways which may be involved in the progression of pancreatic cancer.
Collapse
Affiliation(s)
- Bao-sheng Wang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China,
| | | | | | | |
Collapse
|
|
48
|
Fredebohm J, Boettcher M, Eisen C, Gaida MM, Heller A, Keleg S, Tost J, Greulich-Bode KM, Hotz-Wagenblatt A, Lathrop M, Giese NA, Hoheisel JD. Establishment and characterization of a highly tumourigenic and cancer stem cell enriched pancreatic cancer cell line as a well defined model system. PLoS One 2012; 7:e48503. [PMID: 23152778 PMCID: PMC3495919 DOI: 10.1371/journal.pone.0048503] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 09/26/2012] [Indexed: 12/12/2022] Open
Abstract
Standard cancer cell lines do not model the intratumoural heterogeneity situation sufficiently. Clonal selection leads to a homogeneous population of cells by genetic drift. Heterogeneity of tumour cells, however, is particularly critical for therapeutically relevant studies, since it is a prerequisite for acquiring drug resistance and reoccurrence of tumours. Here, we report the isolation of a highly tumourigenic primary pancreatic cancer cell line, called JoPaca-1 and its detailed characterization at multiple levels. Implantation of as few as 100 JoPaca-1 cells into immunodeficient mice gave rise to tumours that were histologically very similar to the primary tumour. The high heterogeneity of JoPaca-1 was reflected by diverse cell morphology and a substantial number of chromosomal aberrations. Comparative whole-genome sequencing of JoPaca-1 and BxPC-3 revealed mutations in genes frequently altered in pancreatic cancer. Exceptionally high expression of cancer stem cell markers and a high clonogenic potential in vitro and in vivo was observed. All of these attributes make this cell line an extremely valuable model to study the biology of and pharmaceutical effects on pancreatic cancer.
Collapse
MESH Headings
- AC133 Antigen
- Aldehyde Dehydrogenase 1 Family
- Alleles
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antimetabolites, Antineoplastic/pharmacology
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/pharmacology
- Disease Models, Animal
- Drug Resistance, Neoplasm/genetics
- GPI-Linked Proteins/genetics
- GPI-Linked Proteins/metabolism
- Genomic Instability
- Glycoproteins/genetics
- Glycoproteins/metabolism
- Humans
- Isoenzymes/genetics
- Isoenzymes/metabolism
- Keratins/genetics
- Keratins/metabolism
- Male
- Mesothelin
- Mice
- Middle Aged
- Mutation
- Neoplasm Metastasis
- Neoplastic Stem Cells/metabolism
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Peptides/genetics
- Peptides/metabolism
- Polyploidy
- Retinal Dehydrogenase/genetics
- Retinal Dehydrogenase/metabolism
- Transplantation, Heterologous
- Tumor Microenvironment
- Gemcitabine
Collapse
Affiliation(s)
- Johannes Fredebohm
- Functional Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Jiang P, Zang W, Wang L, Xu Y, Liu Y, Deng SX. Protein-protein interaction and SNP analysis in intraductal papillary mucinous neoplasm. Gene 2012; 513:219-24. [PMID: 23107772 DOI: 10.1016/j.gene.2012.10.047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 06/04/2012] [Accepted: 10/10/2012] [Indexed: 12/17/2022]
Abstract
Intraductal papillary mucinous neoplasm (IPMN) is a type of tumor that grows within the pancreatic ducts. It is a progress from hyperplasia to intraductal adenoma (IPMA), to noninvasive carcinoma, and ultimately to invasive carcinoma (IPMC). The objective of this study was to explore the molecular mechanism of the progression from IPMA to IPMC. By using the GSE19650 affymetrix microarray data accessible from Gene Expression Omnibus (GEO) database, we first identified the differentially expressed genes (DEGs) between IPMA and IPMC, followed by the protein-protein interaction and single-nucleotide polymorphism (SNP) analysis of the DEGs. Our study identified thousands of DEGs which involved regulation of cell cycle and apoptosis in this progression from IPMA to IPMC. Protein-protein interaction network construction found that MYC, IL6ST, NR3C1, CREBBP, GATA1 and LRP1 might play an important role in the progression. Furthermore, the SNP analysis confirmed the association between BRAC1 and pancreas cancer. In conclusion, our data provide a comprehensive bioinformatics analysis of genes and pathways which may be involved in the progression of IPMN from IPMA to IPMC.
Collapse
Affiliation(s)
- Pu Jiang
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, China
| | | | | | | | | | | |
Collapse
|
|
50
|
Noh JM, Choi DH, Baek H, Nam SJ, Lee JE, Kim JW, Ki CS, Park W, Huh SJ. Associations between BRCA Mutations in High-Risk Breast Cancer Patients and Familial Cancers Other than Breast or Ovary. J Breast Cancer 2012; 15:283-7. [PMID: 23091540 PMCID: PMC3468781 DOI: 10.4048/jbc.2012.15.3.283] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2012] [Accepted: 05/28/2012] [Indexed: 02/06/2023] Open
Abstract
PURPOSE We investigated the relationship between BRCA mutations and the distribution of familial cancers other than breast or ovary in high-risk breast cancer patients. METHODS PATIENTS WITH BREAST CANCER WHO HAD AT LEAST ONE OF THE FOLLOWING RISK FACTORS WERE ENROLLED: reported family history of breast or ovarian cancer; 40 years of age or younger age at diagnosis; bilateral breast cancer; or male gender. Genetic testing for BRCA mutation and questionnaires about personal and family histories of malignancies were performed. RESULTS Among the 238 eligible patients, 49 (20.6%) patients had BRCA1/2 mutations, which were more frequent in patients with multiple risk factors (p<0.0001). There were 271 members of 156 (65.5%) families who had histories of other primary cancer. The distribution of the families was 119 (63.0%) and 37 (75.5%) in the BRCA-negative and positive group, respectively (p=0.0996). Multiple familial cancers occurred in 70 families, which were significantly more frequent in BRCA-positive families (p=0.0034). By ordinal logistic regression, the occurrence of multiple familial cancers was associated with BRCA mutations (p=0.0045), not with other risk factors. The most common site of disease was the stomach, which is the most common in nationwide. And the proportional incidence of pancreatic cancer (6.8%) was significantly higher than that of nationwide cancer statistics (2.4%, p=0.0137). CONCLUSION BRCA mutations in high-risk breast cancer patients were associated with multiple risk factors and multiple family members with other primary cancers. Genetic counseling based on accurate information should be provided to families with BRCA mutation carriers.
Collapse
Affiliation(s)
- Jae Myoung Noh
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | | | | | | | | | | | | | | |
Collapse
|