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Limijadi EKS, Muniroh M, Prajoko YW, Tjandra KC, Respati DRP. The role of germline BRCA1 & BRCA2 mutations in familial pancreatic cancer: A systematic review and meta-analysis. PLoS One 2024; 19:e0299276. [PMID: 38809921 PMCID: PMC11135687 DOI: 10.1371/journal.pone.0299276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/15/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND Familial Pancreatic Cancer (FPC) presents a notable risk, with 3-10% of pancreatic adenocarcinoma cases having a family history. Studies link FPC to syndromes like HBOC, suggesting BRCA1/BRCA2 mutations play a role. BRCA gene functions in DNA repair impact FPC management, influencing sensitivity to therapies like PARP inhibitors. Identifying mutations not only aids FPC treatment but also reveals broader cancer risks. However, challenges persist in selectively applying genetic testing due to cost constraints. This Systematic Review focuses on BRCA1/BRCA2 significance in FPC, diagnostic criteria, prognostic value, and limitations. METHOD Original articles published from 2013 to January 2023 were sourced from databases such as Scopus, PubMed, ProQuest, and ScienceDirect. Inclusion criteria comprised observational cohort or diagnostic studies related to the role of BRCA1/2 mutation in correlation to familial pancreatic cancer (FPC), while article reviews, narrative reviews, and non-relevant content were excluded. The assessment of bias used ROBINS-I, and the results were organized using PICOS criteria in a Google spreadsheet table. The systematic review adhered to the PRISMA 2020 checklist. RESULT We analyzed 9 diagnostic studies encompassing 1325 families and 4267 patients from Italy, USA, and Poland. Despite the limitation of limited homogenous PICO studies, our findings effectively present evidence. BRCA1/2 demonstrates benefits in detecting first-degree relatives FPC involvement with 2.26-10 times higher risk. These mutation findings also play an important role since with the BRCA1/2 targeted therapy, Poly-ADP Ribose Polymerase inhibitors (PARP) may give better outcomes of FPC treatment. Analysis of BRCA1 and BRCA2 administration's impact on odds ratio (OR) based on six and five studies respectively. BRCA1 exhibited non-significant effects (OR = 1.26, P = 0.51), while BRCA2 showed significance (OR = 1.68, P = 0.04). No heterogeneity observed, indicating consistent results. Further research on BRCA1 is warranted. CONCLUSION Detecting the BRCA1/2 mutation gene offers numerous advantages, particularly in its correlation with FPC. For diagnostic and prognostic purposes, testing is strongly recommended for first-degree relatives, who face a significantly higher risk (2.26-10 times) of being affected. Additionally, FPC patients with identified BRCA1/2 mutations exhibit a more favorable prognosis compared to the non-mutated population. This is attributed to the availability of targeted BRCA1/2 therapy, which maximizes treatment outcomes.
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Affiliation(s)
- Edward Kurnia Setiawan Limijadi
- Doctoral Study Program of Medical and Health Science, Universitas Diponegoro, Semarang, Indonesia
- Faculty of Medicine, Department of Clinical Pathology, Universitas Diopnegoro, Semarang, Indonesia
| | - Muflihatul Muniroh
- Faculty of Medicine, Department of Physiology, Universitas Diponegoro, Semarang, Indonesia
| | - Yan Wisnu Prajoko
- Faculty of Medicine, Department of Surgical Oncology, Universitas Diponegoro, Semarang, Indonesia
- Kariadi General Hospital, Semarang, Indonesia
| | - Kevin Christian Tjandra
- Kariadi General Hospital, Semarang, Indonesia
- Faculty of Medicine, Departement of Medicine, Universitas Diponegoro, Semarang, Indonesia
| | - Danendra Rakha Putra Respati
- Kariadi General Hospital, Semarang, Indonesia
- Faculty of Medicine, Departement of Medicine, Universitas Diponegoro, Semarang, Indonesia
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Palihati M, Iwasaki H, Tsubouchi H. Analysis of the indispensable RAD51 cofactor BRCA2 in Naganishia liquefaciens, a Basidiomycota yeast. Life Sci Alliance 2024; 7:e202302342. [PMID: 38016757 PMCID: PMC10684384 DOI: 10.26508/lsa.202302342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/16/2023] [Accepted: 11/20/2023] [Indexed: 11/30/2023] Open
Abstract
The BRCA2 tumor suppressor plays a critical role in homologous recombination by regulating RAD51, the eukaryotic homologous recombinase. We identified the BRCA2 homolog in a Basidiomycota yeast, Naganishia liquefaciens BRCA2 homologs are found in many Basidiomycota species but not in Ascomycota species. Naganishia BRCA2 (Brh2, for BRCA2 homolog) is about one-third the size of human BRCA2. Brh2 carries three potential BRC repeats with two oligonucleotide/oligosaccharide-binding domains. The homolog of DSS1, a small acidic protein serving as an essential partner of BRCA2 was also identified. The yeast two-hybrid assay shows the interaction of Brh2 with both Rad51 and Dss1. Unlike human BRCA2, Brh2 is not required for normal cell growth, whereas loss of Dss1 results in slow growth. The loss of Brh2 caused pronounced sensitivity to UV and ionizing radiation, and their HR ability, as assayed by gene-targeting efficiency, is compromised. These phenotypes are indistinguishable from those of the rad51 mutant, and the rad51 brh2 double mutant. Naganishia Brh2 is likely the BRCA2 ortholog that functions as an indispensable auxiliary factor for Rad51.
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Affiliation(s)
- Maierdan Palihati
- Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
| | - Hiroshi Iwasaki
- Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
| | - Hideo Tsubouchi
- Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan
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Pantaleo A, Forte G, Fasano C, Lepore Signorile M, Sanese P, De Marco K, Di Nicola E, Latrofa M, Grossi V, Disciglio V, Simone C. Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review. Cancers (Basel) 2023; 16:56. [PMID: 38201484 PMCID: PMC10778202 DOI: 10.3390/cancers16010056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. While population-wide screening recommendations for PDAC in asymptomatic individuals are not achievable due to its relatively low incidence, pancreatic cancer surveillance programs are recommended for patients with germline causative variants in PDAC susceptibility genes or a strong family history. In this study, we sought to determine the prevalence and significance of germline alterations in major genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, TP53) involved in PDAC susceptibility. We performed a systematic review of PubMed publications reporting germline variants identified in these genes in PDAC patients. Overall, the retrieved articles included 1493 PDAC patients. A high proportion of these patients (n = 1225/1493, 82%) were found to harbor alterations in genes (ATM, BRCA1, BRCA2, PALB2) involved in the homologous recombination repair (HRR) pathway. Specifically, the remaining PDAC patients were reported to carry alterations in genes playing a role in other cancer pathways (CDKN2A, STK11, TP53; n = 181/1493, 12.1%) or in the mismatch repair (MMR) pathway (MLH1, MSH2, MSH6, PMS2; n = 87/1493, 5.8%). Our findings highlight the importance of germline genetic characterization in PDAC patients for better personalized targeted therapies, clinical management, and surveillance.
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Affiliation(s)
- Antonino Pantaleo
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Giovanna Forte
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Paola Sanese
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Katia De Marco
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Elisabetta Di Nicola
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Marialaura Latrofa
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Vittoria Disciglio
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology-IRCCS “Saverio de Bellis” Research Hospital, 70013 Bari, Italy; (A.P.); (G.F.); (C.F.); (M.L.S.); (P.S.); (K.D.M.); (E.D.N.); (M.L.); (V.G.)
- Medical Genetics, Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
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Keane F, O’Connor CA, Park W, Seufferlein T, O’Reilly EM. Pancreatic Cancer: BRCA Targeted Therapy and Beyond. Cancers (Basel) 2023; 15:2955. [PMID: 37296917 PMCID: PMC10251879 DOI: 10.3390/cancers15112955] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/18/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.
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Affiliation(s)
- Fergus Keane
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (F.K.); (C.A.O.); (W.P.)
- David M. Rubenstein Center for Pancreatic Cancer Research, New York, NY 10065, USA
| | - Catherine A. O’Connor
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (F.K.); (C.A.O.); (W.P.)
- David M. Rubenstein Center for Pancreatic Cancer Research, New York, NY 10065, USA
| | - Wungki Park
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (F.K.); (C.A.O.); (W.P.)
- David M. Rubenstein Center for Pancreatic Cancer Research, New York, NY 10065, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Thomas Seufferlein
- Department of Internal Medicine, Ulm University Hospital, 89081 Ulm, Germany;
| | - Eileen M. O’Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; (F.K.); (C.A.O.); (W.P.)
- David M. Rubenstein Center for Pancreatic Cancer Research, New York, NY 10065, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
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Ardeshna DR, Rangwani S, Cao T, Pawlik TM, Stanich PP, Krishna SG. Intraductal Papillary Mucinous Neoplasms in Hereditary Cancer Syndromes. Biomedicines 2022; 10:1475. [PMID: 35884779 PMCID: PMC9313108 DOI: 10.3390/biomedicines10071475] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 11/16/2022] Open
Abstract
Hereditary pancreatic cancer, which includes patients with familial pancreatic cancer (FPC) and hereditary pancreatic cancer syndromes, accounts for about 10% of all pancreatic cancer diagnoses. The early detection of pre-cancerous pancreatic cysts has increasingly become a focus of interest in recent years as a potential avenue to lower pancreatic cancer incidence and mortality. Intraductal papillary mucinous cystic neoplasms (IPMNs) are recognized precursor lesions of pancreatic cancer. IPMNs have high prevalence in patients with hereditary pancreatic cancer and their relatives. While various somatic mutations have been identified in IPMNs, certain germline mutations associated with hereditary cancer syndromes have also been identified in IPMNs, suggesting a role in their formation. While the significance for the higher prevalence of IPMNs or similar germline mutations in these high-risk patients remain unclear, IPMNs do represent pre-malignant lesions that need close surveillance. This review summarizes the available literature on the incidence and prevalence of IPMNs in inherited genetic predisposition syndromes and FPC and speculates if IPMN and pancreatic cancer surveillance in these high-risk individuals needs to change.
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Affiliation(s)
- Devarshi R. Ardeshna
- Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (D.R.A.); (S.R.)
| | - Shiva Rangwani
- Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (D.R.A.); (S.R.)
| | - Troy Cao
- College of Medicine, Ohio State University, Columbus, OH 43210, USA;
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Peter P. Stanich
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Somashekar G. Krishna
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
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Ling C, Hong X, Xu M, Wang Y, Ma X, Cui Y, Jiang R, Cao D, Wu H, Tong A, Zhao Y, Wu W. Convergence between germline and somatic mutations in pancreatic neuroendocrine tumors. Eur J Endocrinol 2022; 187:85-90. [PMID: 35521758 DOI: 10.1530/eje-21-0893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 04/25/2022] [Indexed: 11/08/2022]
Abstract
OBJECTIVES The pancreatic neuroendocrine tumors (PanNETs) are a group of clinically heterogeneous neoplasms. Although previous studies illustrated the somatic mutation pattern for PanNETs, the germline mutation pattern is still unclear. Here, we comprehensively screened the underlying germline mutations in a cohort of multiple endocrine neoplasia type 1 (MEN1)-related and sporadic PanNETs to reveal the characteristics of germline mutation in PanNET patients. METHODS Patients diagnosed with PanNETs by biopsy or surgical pathology were enrolled in this study. Peripheral blood samples were used for genomic DNA purification and subsequent sequencing. The following sequencing techniques were used and compared for validation: (1) targeted gene capture with a customized panel; (2) whole exome sequencing data from previous study. RESULTS A total of 184 PanNET patients were enrolled, including 20 MEN1-related and 164 sporadic cases. In this study, MEN1 mutation rate in MEN1-related PanNETs was 60% (12/20), of which 50% were novel mutation sites. For sporadic PanNETs, the overall germline mutation rate was very low. Besides the rare MEN1 mutation, previously unreported germline variant in DAXX was found in one non-functional PanNET. CONCLUSIONS This study revealed distinctive germline mutation rates between MEN1-related and sporadic PanNETs. The novel MEN1 mutations contribute to revealing the spectrum of MEN1 mutations in PanNETs. The newly discovered germline variant of DAXX in sporadic PanNET implies a tendency of convergence between germline and somatic mutation genes.
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Affiliation(s)
- Chao Ling
- The Laboratory of Clinical Genetics, Medical Research Center
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Xiafei Hong
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Mengyue Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Yutong Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Xiaosen Ma
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Yunying Cui
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Rui Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Dingyan Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Huanwen Wu
- Department of Pathology, Peking Union Medical College Hospital, and Molecular Pathology Research Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Anli Tong
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Wenming Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
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Crowley F, Park W, O'Reilly EM. Targeting DNA damage repair pathways in pancreas cancer. Cancer Metastasis Rev 2021; 40:891-908. [PMID: 34403012 DOI: 10.1007/s10555-021-09983-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 07/30/2021] [Indexed: 02/07/2023]
Abstract
Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients, TRK inhibitors larotrectinib and entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients, and the poly-ADP-ribose polymerase (PARP) inhibitor olaparib in patients with germline BRCA mutation as a maintenance therapy. DNA damage repair (DDR) is paramount to genomic integrity and cell survival. The defective repair of DNA damage is one of the hallmarks of cancer, and abnormalities in DDR pathways are closely linked with the development of malignancies and upregulation of these pathways linked with resistance to treatment. The prevalence of somatic and germline mutations in DDR pathways in metastatic PDAC is reported to be approximately 15-25%. Patients with DDR gene alterations benefit from a personalized approach to treatment. Recently, the POLO trial demonstrated a progression-free survival (PFS) benefit in metastatic PDAC patients with a germline BRCA1/2 mutation treated with maintenance olaparib following platinum-based induction chemotherapy. This was the first phase 3 randomized trial to establish a biomarker-driven approach in the treatment of PDAC and establishes a precedent for maintenance therapy in PDAC. The review herein aims to outline the current treatment landscape for PDAC patients with DDR gene-mutated tumors, highlight novel therapeutic approaches focused on surmounting tumor resistance, and explore new strategies which may lead to an expansion in the number of patients who benefit from these targeted treatments.
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Affiliation(s)
- Fionnuala Crowley
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Office 1021, New York, NY, USA.,Internal Medicine, Mount Sinai Morningside West Hospital Center, New York, NY, USA.,Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Wungki Park
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Office 1021, New York, NY, USA.,David M. Rubenstein Center for Pancreas Research, New York, NY, USA.,Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.,Weill Cornell Medical College, New York, NY, USA
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Office 1021, New York, NY, USA. .,David M. Rubenstein Center for Pancreas Research, New York, NY, USA. .,Weill Cornell Medical College, New York, NY, USA.
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Alkassis S, Yazdanpanah O, Philip PA. BRCA mutations in pancreatic cancer and progress in their targeting. Expert Opin Ther Targets 2021; 25:547-557. [PMID: 34289788 DOI: 10.1080/14728222.2021.1957462] [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: 12/17/2022]
Abstract
Introduction: Genomic instability resulting from DNA damage repair (DDR) deficiencies is a hallmark of cancer and offers treatment opportunities. Homologous recombination DDR defect is a result of multiple critical gene mutations, including BRCA1/2. Targeting DNA DDR defects in pancreatic cancer (PC) is emerging as a potential treatment strategy with current focus on BRCA mutations.Areas covered: Challenges in treating patients with PC are explained. We review DDR defects as a treatment target in PC, specifically, germline BRCA mutation and sensitivity to platinum compounds and exploiting the strategy of synthetic lethality using poly (ADP-ribose) polymerase (PARP) inhibition. Literature review was undertaken through PubMed, Google Scholar, and Clinicaltrials.gov website.Expert opinion: DDR defects are promising targets for novel therapies in PC. Early application of such strategy is in patient subgroup with BRCA germline mutation, which is seen in only 5-7% of the PC population. The oral PARP inhibitor olaparib in the maintenance setting represents the first targeted therapy in metastatic PC based on a phase 3 study. There is a very modest benefit for patients with PC using PARP inhibitors. Future work must improve our understanding of mechanisms of sensitivity and resistance to PARP inhibitors in PC and enhance the molecular selection of patients for such therapy.
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Affiliation(s)
- Samer Alkassis
- Internal Medicine Department, Wayne State University/Detroit Medical Center, Detroit, MI, USA
| | - Omid Yazdanpanah
- Internal Medicine Department, Wayne State University/Detroit Medical Center, Detroit, MI, USA
| | - Philip Agop Philip
- Division of Hematology/Oncology, Karmanos Cancer Institute, Detroit, MI, USA
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Noë M, Hong SM, Wood LD, Thompson ED, Roberts NJ, Goggins MG, Klein AP, Eshleman JR, Kern SE, Hruban RH. Pancreatic cancer pathology viewed in the light of evolution. Cancer Metastasis Rev 2021; 40:661-674. [PMID: 33555482 PMCID: PMC8556193 DOI: 10.1007/s10555-020-09953-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/30/2020] [Indexed: 12/14/2022]
Abstract
One way to understand ductal adenocarcinoma of the pancreas (pancreatic cancer) is to view it as unimaginably large numbers of evolving living organisms interacting with their environment. This “evolutionary view” creates both expected and surprising perspectives in all stages of neoplastic progression. Advances in the field will require greater attention to this critical evolutionary prospective.
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Affiliation(s)
- Michaël Noë
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Laura D Wood
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Elizabeth D Thompson
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
| | - Nicholas J Roberts
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Michael G Goggins
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Alison P Klein
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - James R Eshleman
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Scott E Kern
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Ralph H Hruban
- Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Carnegie 415, 600 North Wolfe Street, Baltimore, MD, 21287, USA.
- Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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10
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Gentiluomo M, Canzian F, Nicolini A, Gemignani F, Landi S, Campa D. Germline genetic variability in pancreatic cancer risk and prognosis. Semin Cancer Biol 2020; 79:105-131. [DOI: 10.1016/j.semcancer.2020.08.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 08/04/2020] [Accepted: 08/06/2020] [Indexed: 02/07/2023]
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11
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Park D, Shakya R, Koivisto C, Pitarresi JR, Szabolcs M, Kladney R, Hadjis A, Mace TA, Ludwig T. Murine models for familial pancreatic cancer: Histopathology, latency and drug sensitivity among cancers of Palb2, Brca1 and Brca2 mutant mouse strains. PLoS One 2019; 14:e0226714. [PMID: 31877165 PMCID: PMC6932818 DOI: 10.1371/journal.pone.0226714] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Abstract
Alterations of the PALB2 tumor suppressor gene have been identified in familial breast, ovarian and pancreatic cancer cases. PALB2 cooperates with BRCA1/2 proteins through physical interaction in initiation of homologous recombination, in maintenance of genome integrity following DNA double-strand breaks. To determine if the role of PALB2 as a linker between BRCA1 and BRCA2 is critical for BRCA1/2-mediated tumor suppression, we generated Palb2 mouse pancreatic cancer models and compared tumor latencies, phenotypes and drug responses with previously generated Brca1/2 pancreatic cancer models. For development of Palb2 pancreatic cancer, we crossed conditional Palb2 null mouse with mice carrying the KrasG12D; p53R270H; Pdx1-Cre (KPC) constructs, and these animals were observed for pancreatic tumor development. Individual deletion of Palb2, Brca1 or Brca2 genes in pancreas per se using Pdx1-Cre was insufficient to cause tumors, but it reduced pancreata size. Concurrent expression of mutant KrasG12D and p53R270H, with tumor suppressor inactivated strains in Palb2-KPC, Brca1-KPC or Brca2-KPC, accelerated pancreatic ductal adenocarcinoma (PDAC) development. Moreover, most Brca1-KPC and some Palb2-KPC animals developed mucinous cystic neoplasms with PDAC, while Brca2-KPC and KPC animals did not. 26% of Palb2-KPC mice developed MCNs in pancreata, which resemble closely the Brca1 deficient tumors. However, the remaining 74% of Palb2-KPC animals developed PDACs without any cysts like Brca2 deficient tumors. In addition, the number of ADM lesions and immune cells infiltrations (CD3+ and F/480+) were significantly increased in Brca1-KPC tumors, but not in Brca2-KPC tumors. Interestingly, the level of ADM lesions and infiltration of CD3+ or F/480+ cells in Palb2-KPC tumors were intermediate between Brca1-KPC and Brca2-KPC tumors. As expected, disruption of Palb2 and Brca1/2 sensitized tumor cells to DNA damaging agents in vitro and in vivo. Altogether, Palb2-KPC PDAC exhibited features observed in both Brca1-KPC and Brca2-KPC tumors, which could be due to its role, as a linker between Brca1 and Brca2.
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Affiliation(s)
- Dongju Park
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Reena Shakya
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Christopher Koivisto
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Jason R Pitarresi
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Matthias Szabolcs
- Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America
| | - Raleigh Kladney
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Ashley Hadjis
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Thomas A Mace
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Thomas Ludwig
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
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12
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Pilarski R. The Role of BRCA Testing in Hereditary Pancreatic and Prostate Cancer Families. Am Soc Clin Oncol Educ Book 2019; 39:79-86. [PMID: 31099688 DOI: 10.1200/edbk_238977] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Beyond breast and ovarian cancers, mutations in the BRCA1 and BRCA2 genes increase risks for pancreatic and prostate cancers and contribute to the prevalence of these cancers. Mutations in a number of other genes have also been shown to increase the risk for these cancers as well. Genetic testing is playing an increasingly important role in the treatment of patients with pancreatic and prostate cancer and is now recommended for all patients with pancreatic or metastatic prostate cancer, as well as patients with high Gleason grade prostate cancer and a remarkable family history. Identification of an inherited mutation can direct evaluation of the patient for other cancer risks as well as identification and management of disease in at-risk relatives. Growing evidence suggests improved responses to PARP inhibitors and other therapies in patients with mutations in the BRCA and other DNA repair genes. Although more work must be done to clarify the prevalence and penetrance of mutations in genes other than BRCA1 and BRCA2 in patients with pancreatic and prostate cancer, in most cases, testing is now being done with a panel of multiple genes. Because of the complexities in panel testing and the increased likelihood of finding variants of uncertain significance, pre- and post-test genetic counseling are essential.
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Affiliation(s)
- Robert Pilarski
- 1 Division of Human Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH
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13
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Wood LD, Yurgelun MB, Goggins MG. Genetics of Familial and Sporadic Pancreatic Cancer. Gastroenterology 2019; 156:2041-2055. [PMID: 30660730 DOI: 10.1053/j.gastro.2018.12.039] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 11/14/2018] [Accepted: 12/05/2018] [Indexed: 12/14/2022]
Abstract
In the previous decade, comprehensive genomic analyses have yielded important insights about the genetic alterations that underlie pancreatic tumorigenesis. Whole-exome and whole-genome sequencing of pancreatic ductal adenocarcinomas have confirmed the critical driver genes altered in the majority of pancreatic cancers, as well as identified numerous less frequently altered driver genes, and have delineated cancer subgroups with unique biological and clinical features. It is now appreciated that pancreatic susceptibility gene alterations are often identified in patients with pancreatic cancer without family histories suggestive of a familial cancer syndrome, prompting recent efforts to expand gene testing to all patients with pancreatic cancer. Studies of pancreatic cancer precursor lesions have begun to elucidate the evolutionary history of pancreatic tumorigenesis and to help us understand the utility of biomarkers for early detection and targets to develop new therapeutic strategies. In this review, we discuss the results of comprehensive genomic characterization of pancreatic ductal adenocarcinoma and its precursor lesions, and we highlight translational applications in early detection and therapy.
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Affiliation(s)
- Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Matthew B Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
| | - Michael G Goggins
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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14
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Characteristics and Clinical Outcomes of Individuals at High Risk for Pancreatic Cancer: A Descriptive Analysis from a Comprehensive Cancer Center. GASTROINTESTINAL DISORDERS 2019; 1:106-119. [PMID: 32601617 PMCID: PMC7324042 DOI: 10.3390/gidisord1010008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pancreatic cancer (PC), a leading cause of cancer-related deaths in the United States, is typically diagnosed at an advanced stage. To improve survival, there is an unmet need to detect pre-malignant lesions and early invasive disease. Prime populations to study for early detection efforts include cohorts of high risk individuals (HRI): those with increased risk to develop pre-malignant pancreatic cysts and PC because of a familial or hereditary predisposition to the disease and those in the general population of sporadic cases who are incidentally found to harbor a pre-malignant pancreatic cyst. The objective of this study was to describe the characteristics and clinical outcomes of cohorts of HRI identified at Moffitt Cancer Center. We set out to determine the uptake of screening, the prevalence and characteristics of solid and cystic pancreatic lesions detected via screening or as incidental findings, and the age at which lesions were detected. Of a total of 329 HRI, roughly one-third were found to have pancreatic lesions, most of which constituted pre-malignant cysts known as intraductal papillary mucinous neoplasms. Individuals with the highest genetic risk for PC were found to have smaller cysts at a much earlier age than sporadic cases with incidental findings; however, many individuals at high genetic risk did not have abdominal imaging reports on file. We also identified a subset of HRI at moderate genetic risk for PC that were found to have cystic and solid pancreatic lesions as part of a diagnostic work-up rather than a screening protocol. These findings suggest the pancreatic research community should consider expanding criteria for who should be offered screening. We also emphasize the importance of continuity of care between cancer genetics and gastrointestinal oncology clinics so that HRI are made aware of the opportunities related to genetic counseling, genetic testing, and screening.
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15
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Yeo TP, Lavu H, Nevler A, Brumbaugh J, Vicchairelli D, Winter JM, Brody JR, Yeo CJ. Precious Data: Interim Report from the Jefferson Pancreas Tumor Registry. J Pancreat Cancer 2019; 4:17-24. [PMID: 30631853 PMCID: PMC6145534 DOI: 10.1089/pancan.2018.0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Purpose: The Jefferson Pancreas Tumor Registry (JPTR) is a voluntary hospital-based registry of persons with pancreas and related periampullary cancers, premalignant lesions, and nonaffected family members (NAFMs). The ultimate goals of the JPTR are to provide a link between family history, gene mutations, and precision medicine therapy, and to identify high-risk NAFMs for potential surveillance screening. Methods: The JPTR is an Institutional Review Board approved longitudinal epidemiological study housed in the Department of Surgery at Thomas Jefferson University Hospital. Individuals who met the eligibility criteria and signed informed consent provide information on hereditary conditions, family history of cancers, environmental exposures, and occupational risk factors. Data are collected using a self-administered questionnaire, the electronic medical record, and the molecular analysis of tumor specimens. Results: Established in 2008, >725 persons have enrolled in the JPTR. The cohort is mostly composed of sporadic pancreas cancer, with 13% of enrollees having familial pancreas cancer and a control group comprising nonaffected persons. Data from the registry have been utilized to inform clinical studies, molecular investigations, and to shed light on and gain insight into the lived experience of persons with these conditions. Conclusion: The JPTR contains precious qualitative data and is an invaluable repository of information about persons with pancreatic and related tumors.
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Affiliation(s)
- Theresa P Yeo
- Department of Surgery and the Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania.,Thomas Jefferson University, Jefferson College of Nursing, Philadelphia, Pennsylvania
| | - Harish Lavu
- Department of Surgery and the Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania
| | - Avinoam Nevler
- Department of Surgery and the Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania.,The Dr. P. Borenstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Israel
| | - Jennifer Brumbaugh
- Department of Surgery and the Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania
| | - Dominique Vicchairelli
- Department of Surgery and the Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania
| | - Jordan M Winter
- Department of Surgery and the Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania
| | - Jonathan R Brody
- Department of Surgery and the Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania
| | - Charles J Yeo
- Department of Surgery and the Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania
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16
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Abstract
Introduction: Both breast and pancreatic cancers have high mortality rates. Breast cancer is the second leading cause of cancer death in females, while pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death. Almost 4-16 % of individuals with pancreatic cancer have a family history of the disease. Intra-ductal papillary mucinous neoplasms (IPMNs) are cystic lesions that received more attention lately due to their associations with PDAC and other solid organ tumors, such as breast cancer. Aim: The purpose of this article is to discuss the association of the familiar pancreatic cancer (FPC), sporadic pancreatic cancer, and IPMNs with the breast cancer. Results: Mutations in BRCA2, BRCA1, p16 and PALB2 play a major role in the genetic etiologies of familial pancreatic cancer. In familial and sporadic pancreatic cancers, mutations in BRCA2 are associated with a high incidence of PDAC, while mutations in BRCA1have shown inconsistent results. Data is insufficient to prove an association between IPMNs and breast cancer. Conclusion: The familial clustering of PDAC is not well understood. Further studies are required for greater comprehension of the genetic basis of PDAC and the association between IPMNs and breast cancer.
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Affiliation(s)
- Mary Barbara
- Department of Medicine, UT Health San Antonio, San Antonio, TX, USA
| | - Adrianne Tsen
- Department of Medicine, UT Health San Antonio, San Antonio, TX, USA
| | - Laura Tenner
- Department of Hematology and Oncology, UT Health San Antonio, San Antonio, Tx, USA
| | - Laura Rosenkranz
- Department of Gastroenterology, UT Health San Antonio San Antonio, TX, USA
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17
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Zhan W, Shelton CA, Greer PJ, Brand RE, Whitcomb DC. Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts. Pancreas 2018; 47:924-936. [PMID: 30113427 PMCID: PMC6097243 DOI: 10.1097/mpa.0000000000001136] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants and environmental factors may increase the risk of cancer and accelerate the oncogenic process. We systematically reviewed, annotated, and classified previously reported pancreatic cancer-associated germline variants in established risk genes. Variants were scored using multiple criteria and binned by evidence for pathogenicity, then annotated with published functional studies and associated biological systems/pathways. Twenty-two previously identified pancreatic cancer risk genes and 337 germline variants were identified from 97 informative studies that met our inclusion criteria. Fifteen of these genes contained 66 variants predicted to be pathogenic (APC, ATM, BRCA1, BRCA2, CDKN2A, CFTR, CHEK2, MLH1, MSH2, NBN, PALB2, PALLD, PRSS1, SPINK1, TP53). Pancreatic cancer risk genes were organized into key biological mechanisms that promote pancreatic oncogenesis within an oncogenic model. Development of precision medicine approaches requires updated variant information within the framework of an oncogenic progression model. Complex risk modeling may improve interpretation of early biomarkers and guide pathway-specific treatment for pancreatic cancer in the future. Precision medicine is within reach.
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Affiliation(s)
- Wei Zhan
- School of Medicine, Tsinghua University, Beijing, China
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, and University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Celeste A. Shelton
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, and University of Pittsburgh Medical Center, Pittsburgh, PA
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Phil J. Greer
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, and University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Randall E. Brand
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, and University of Pittsburgh Medical Center, Pittsburgh, PA
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - David C. Whitcomb
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, and University of Pittsburgh Medical Center, Pittsburgh, PA
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
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18
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Sikdar N, Saha G, Dutta A, Ghosh S, Shrikhande SV, Banerjee S. Genetic Alterations of Periampullary and Pancreatic Ductal Adenocarcinoma: An Overview. Curr Genomics 2018; 19:444-463. [PMID: 30258276 PMCID: PMC6128383 DOI: 10.2174/1389202919666180221160753] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 01/31/2018] [Accepted: 02/01/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies of all solid cancers. Precancerous lesions for PDAC include PanIN, IPMNs and MCNs. PDAC has a poor prognosis with a 5-year survival of approximately 6%. Whereas Periampulary AdenoCarcinoma (PAC) having four anatomic subtypes, pancreatic, Common Bile Duct (CBD), ampullary and duodenum shows relative better prognosis. The highest incidence of PDAC has been reported with black with respect to white population. Similarly, incidence rate of PAC also differs with different ethnic populations. Several lifestyle, environmental and occupational exposures including long-term diabetes, obesity, and smoking, have been linked to PDAC, however, for PAC the causal risk factors were poorly described. It is now clear that PDAC and PAC are a multi-stage process resulting from the accumulation of genomic alterations in the somatic DNA of normal cells as well as inherited mutations. Approximately 10% of PDAC have a familial inheritance. Germline mutations in CDKN2A, BRCA2, STK11, PALB2, PRSS1, etc., as well as certain syndromes have been well associated with predisposition to PDAC. KRAS, CDKN2A, TP53 and SMAD4 are the 4 "mountains" (high-frequency driver genes) which have been known to earliest somatic alterations for PDAC while relatively less frequent in PAC. Our understanding of the molecular carcinogenesis has improved in the last few years due to extensive research on PDAC which was not well explored in case of PAC. The genetic alterations that have been identified in PDAC and different subgroups of PAC are important implications for the development of genetic screening test, early diagnosis, and prognostic genetic markers. The present review will provide a brief overview of the incidence and prevalence of PDAC and PAC, mainly, increased risk in India, the several kinds of risk factors associated with the diseases as well as required genetic alterations for disease initiation and progression.
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Affiliation(s)
- Nilabja Sikdar
- Address correspondence to this author at the Human Genetics Unit, Indian Statistical Institute, 203, B.T. Road Kolkata 700108, India; Tel (1): +91-33
-25773240 (L); (2): +91-9830780397 (M); Fax: +91 33 35773049;, E-mail:
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19
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Dudley B, Karloski E, Monzon FA, Singhi AD, Lincoln SE, Bahary N, Brand RE. Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy. Cancer 2018; 124:1691-1700. [PMID: 29360161 DOI: 10.1002/cncr.31242] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 11/22/2017] [Accepted: 12/29/2017] [Indexed: 12/17/2023]
Abstract
BACKGROUND Approximately 10% of pancreatic adenocarcinoma (PC) cases are attributed to hereditary causes. Individuals with PC and a personal history of another cancer associated with hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS) may be more likely to carry germline mutations. METHODS Participants with PC and a history of cancer were selected from a pancreatic disease registry. Of 1296 individuals with PC, 149 had a relevant history of cancer. If banked DNA was available, a multigene panel was performed for individuals who had not 1) previously had a mutation identified through clinical testing or 2) undergone clinical multigene panel testing with no mutations detected. RESULTS Twenty-two of 124 individuals with PC and another HBOC- or LS-related cancer who underwent genetic testing had a mutation identified in a PC susceptibility gene (18%). If prostate cancer is excluded, the mutation prevalence increased to 23% (21/93). Mutation carriers were more likely to have more than 1 previous cancer diagnosis (P = .001), to have had clinical genetic testing (P = .001), and to meet National Comprehensive Cancer Network (NCCN) genetic testing criteria (P < .001). Approximately 23% of mutation carriers did not meet NCCN HBOC or LS testing guidelines based on their personal cancer history and reported cancer history in first-degree relatives. CONCLUSION At least 18% of individuals with PC and a personal history of other HBOC- or LS-related cancers carry mutations in a PC susceptibility gene based on our data, suggesting that criteria for genetic testing in individuals with PC should include consideration of previous cancer history. Cancer 2018;124:1691-700. © 2018 American Cancer Society.
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Affiliation(s)
- Beth Dudley
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Eve Karloski
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | | | - Nathan Bahary
- Department of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Randall E Brand
- Department of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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20
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Abstract
PURPOSE OF REVIEW This review describes the rationale for pancreatic cancer screening, outlines groups that are at elevated risk for pancreatic cancer, and summarizes the relative risk in each setting. We also review the methods available for performing pancreatic cancer screening and the recommended screening intervals. RECENT FINDINGS Several genetic mutations have been identified that increase the risk for pancreatic cancer. Most are rare, however, and at-risk individuals are most often those with a strong family history of pancreatic cancer (with multiple family members affected) but no identifiable genetic mutation. Known genetic syndromes that increase the risk for pancreatic cancer include hereditary pancreatitis, familial atypical mole and multiple melanoma, Peutz-Jeghers syndrome, Lynch syndrome, BRCA mutations, and Li-Fraumeni syndrome. Genetic testing should be performed in conjunction with genetic counseling, and testing of an affected family member is preferred if possible.The goal of pancreatic cancer screening is to identify pancreatic cancer at an early, curable stage or, ideally, to identify precancerous lesions that can be resected to prevent the development of cancer. Imaging can be performed with either endoscopic ultrasound (EUS) or magnetic resonance cholangiopancreatography (MRCP). These techniques are generally considered to be complementary, although an advantage of EUS is that cysts or solid lesions can be sampled at the time of the procedure. Published results of small cohorts of high-risk patients in pancreatic cancer screening programs have demonstrated a high prevalence of small cystic lesions identified on EUS or MRCP, which often represent side-branch intraductal papillary mucinous neoplasms (IPMN). Knowledge of conditions and syndromes that increase pancreatic cancer risk allows one to identify those patients that may benefit from pancreatic cancer screening. As we gather evidence from large, international, multicenter cohorts of patients at high-risk for pancreatic cancer who are undergoing screening and as our understanding of the genetic underpinnings of pancreatic cancer improve, recommendations on screening will continue to be refined.
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Affiliation(s)
- Koushik K Das
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue Campus, Box 8124, St. Louis, MO, 63110-1093, USA.
| | - Dayna Early
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue Campus, Box 8124, St. Louis, MO, 63110-1093, USA
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21
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Wu H, Wu X, Liang Z. Impact of germline and somatic BRCA1/2 mutations: tumor spectrum and detection platforms. Gene Ther 2017; 24:601-609. [PMID: 28771233 DOI: 10.1038/gt.2017.73] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 07/10/2017] [Accepted: 07/27/2017] [Indexed: 12/13/2022]
Abstract
The BRCA1/2 genes are long and complex and mutation carriers are at risk of developing malignancies, mainly of gynecological origin. Various mutations arise in these genes and their characterization is a time-consuming, cost intensive, complicated process. Tumors of BRCA1/2 origin have distinct molecular and histological features that can impact responses to therapy. Therefore, detection of these mutations constitutes an important step in the risk assessment, prevention strategy and treatment of subjects. Although Sanger sequencing is the gold standard for the detection of genetic mutations, several next generation sequencing-based high throughput platforms have been developed and adapted for the detection of BRCA1/2 mutations. This review provides a comprehensive overview of the sequencing platforms available for the screening and identification of these mutations. We also summarize what is known about the different types of mutations that arise in these genes and the tumor spectra they result in. Finally, we present a short discussion on existing clinical guidelines which assist physicians in the decision-making process. These parameters have important consequences for the management of patients and an urgent need exists for the development of detection platforms that are cost effective and can provide clinicians with conclusive results within a significantly shorter time.
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Affiliation(s)
- H Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - X Wu
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Z Liang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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22
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Shindo K, Yu J, Suenaga M, Fesharakizadeh S, Cho C, Macgregor-Das A, Siddiqui A, Witmer PD, Tamura K, Song TJ, Navarro Almario JA, Brant A, Borges M, Ford M, Barkley T, He J, Weiss MJ, Wolfgang CL, Roberts NJ, Hruban RH, Klein AP, Goggins M. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol 2017; 35:3382-3390. [PMID: 28767289 DOI: 10.1200/jco.2017.72.3502] [Citation(s) in RCA: 324] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean ± SD, 60.8 ± 10.6 v 65.1 ± 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.
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Affiliation(s)
- Koji Shindo
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Jun Yu
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Masaya Suenaga
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Shahriar Fesharakizadeh
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Christy Cho
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Anne Macgregor-Das
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Abdulrehman Siddiqui
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - P Dane Witmer
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Koji Tamura
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Tae Jun Song
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | | | - Aaron Brant
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Michael Borges
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Madeline Ford
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Thomas Barkley
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Jin He
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Matthew J Weiss
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Christopher L Wolfgang
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Nicholas J Roberts
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Ralph H Hruban
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Alison P Klein
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
| | - Michael Goggins
- All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD
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Inactivation of BRCA2 in human cancer cells identifies a subset of tumors with enhanced sensitivity towards death receptor-mediated apoptosis. Oncotarget 2017; 7:9477-90. [PMID: 26843614 PMCID: PMC4891053 DOI: 10.18632/oncotarget.7053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Accepted: 01/01/2016] [Indexed: 12/20/2022] Open
Abstract
Purpose DNA repair defects due to detrimental BRCA2-mutations confer increased susceptibility towards DNA interstrand-crosslinking (ICL) agents and define patient subpopulations for individualized genotype-based cancer therapy. However, due to the side effects of these drugs, there is a need to identify additional agents, which could be used alone or in combination with ICL-agents. Therefore, we investigated whether BRCA2-mutations might also increase the sensitivity towards TRAIL-receptors (TRAIL-R)-targeting compounds. Experimental design Two independent model systems were applied: a BRCA2 gene knockout and a BRCA2 gene complementation model. The effects of TRAIL-R-targeting compounds and ICL-agents on cell viability, apoptosis and cell cycle distribution were compared in BRCA2-proficient versus-deficient cancer cells in vitro. In addition, the effects of the TRAIL-R2-targeting antibody LBY135 were assessed in vivo using a murine tumor xenograft model. Results BRCA2-deficient cancer cells displayed an increased sensitivity towards TRAIL-R-targeting agents. These effects exceeded and were mechanistically distinguishable from the well-established effects of ICL-agents. In vitro, ICL-agents expectedly induced an early cell cycle arrest followed by delayed apoptosis, whereas TRAIL-R-targeting compounds caused early apoptosis without prior cell cycle arrest. In vivo, treatment with LBY135 significantly reduced the tumor growth of BRCA2-deficient cancer cells in a xenograft model. Conclusions BRCA2 mutations strongly increase the in vitro- and in vivo-sensitivity of cancer cells towards TRAIL-R-mediated apoptosis. This effect is mechanistically distinguishable from the well-established ICL-hypersensitivity of BRCA2-deficient cells. Our study thus defines a new genetic subpopulation of cancers susceptible towards TRAIL-R-targeting compounds, which could facilitate novel therapeutic approaches for patients with BRCA2-deficient tumors.
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Pathogenic Mutations in Cancer-Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records. PLoS One 2016; 11:e0167847. [PMID: 27930734 PMCID: PMC5145192 DOI: 10.1371/journal.pone.0167847] [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: 07/27/2016] [Accepted: 11/21/2016] [Indexed: 12/20/2022] Open
Abstract
Background It is unclear whether and how whole-genome sequencing (WGS) data can be used to implement genomic medicine. Our objective is to retrospectively evaluate whether WGS can facilitate improving prevention and care for patients with susceptibility to cancer syndromes. Methods and Findings We analyzed genetic mutations in 60 autosomal dominant cancer-predisposition genes in 300 deceased patients with WGS data and nearly complete long-term (over 30 years) medical records. To infer biological insights from massive amounts of WGS data and comprehensive clinical data in a short period of time, we developed an in-house analysis pipeline within the SeqHBase software framework to quickly identify pathogenic or likely pathogenic variants. The clinical data of the patients who carried pathogenic and/or likely pathogenic variants were further reviewed to assess their clinical conditions using their lifetime EHRs. Among the 300 participants, 5 (1.7%) carried pathogenic or likely pathogenic variants in 5 cancer-predisposing genes: one in APC, BRCA1, BRCA2, NF1, and TP53 each. When assessing the clinical data, each of the 5 patients had one or more different types of cancers, fully consistent with their genetic profiles. Among these 5 patients, 2 died due to cancer while the others had multiple disorders later in their lifetimes; however, they may have benefited from early diagnosis and treatment for healthier lives, had the patients had genetic testing in their earlier lifetimes. Conclusions We demonstrated a case study where the discovery of pathogenic or likely pathogenic germline mutations from population-wide WGS correlates with clinical outcome. The use of WGS may have clinical impacts to improve healthcare delivery.
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Dhillon KK, Bajrami I, Taniguchi T, Lord CJ. Synthetic lethality: the road to novel therapies for breast cancer. Endocr Relat Cancer 2016; 23:T39-55. [PMID: 27528623 DOI: 10.1530/erc-16-0228] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 08/15/2016] [Indexed: 12/12/2022]
Abstract
When the BRCA1 and BRCA2 tumour suppressor genes were identified in the early 1990s, the immediate implications of mapping, cloning and delineating the sequence of these genes were that individuals in families with a BRCA gene mutation could be tested for the presence of a mutation and their risk of developing cancer could be predicted. Over time though, the discovery of BRCA1 and BRCA2 has had a much greater influence than many might have imagined. In this review, we discuss how the discovery of BRCA1 and BRCA2 has not only provided an understanding of the molecular processes that drive tumourigenesis but also reignited an interest in therapeutically exploiting loss-of-function alterations in tumour suppressor genes.
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Affiliation(s)
| | - Ilirjana Bajrami
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research CentreThe Institute of Cancer Research, London, UK
| | | | - Christopher J Lord
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research CentreThe Institute of Cancer Research, London, UK
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Foulkes WD, Sugano K. BRCA2: a grown-up cancer susceptibility gene. Endocr Relat Cancer 2016; 23:E1-3. [PMID: 27650115 DOI: 10.1530/erc-16-0354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 08/12/2016] [Indexed: 11/08/2022]
Affiliation(s)
- William D Foulkes
- Departments of Human GeneticsMedicine and Oncology, McGill University, Montreal, Quebec, Canada
| | - Kokichi Sugano
- Oncogene Research Unit/Cancer Prevention UnitTochigi Cancer Center Research Institute, Tochigi, Japan
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de Mestier L, Danset JB, Neuzillet C, Rebours V, Cros J, Soufir N, Hammel P. Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers. Endocr Relat Cancer 2016; 23:T57-67. [PMID: 27511924 DOI: 10.1530/erc-16-0269] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 08/10/2016] [Indexed: 12/13/2022]
Abstract
Germline BRCA2 mutations are the first known cause of inherited (familial) pancreatic ductal adenocarcinoma (PDAC). This tumor is the third most frequent cancer in carriers of germline BRCA2 mutations, as it occurs in around 10% of BRCA2 families. PDAC is known as one of the most highly lethal cancers, mainly because of its chemoresistance and frequently late diagnosis. Based on recent developments in molecular biology, a subgroup of BRCA2-associated PDAC has been created, allowing screening, early surgical treatment and personalized systemic treatment. BRCA2 germline mutation carriers who have ≥1 first-degree relative, or ≥2 blood relatives with PDAC, should undergo screening and regular follow-up based on magnetic resonance imaging and endoscopic ultrasound. The goal of screening is to detect early invasive PDAC and advanced precancerous lesions suitable for a stepwise surgical complete (R0) resection. Increasing evidence on the molecular role of the BRCA2 protein in the homologous recombination of DNA damages suggest that BRCA2-related PDAC are sensitive to agents causing DNA cross-linking damage, such as platinum salts, and treatments targeting rescue DNA repair pathways, such as poly(ADP-ribose) polymerase inhibitors that are currently under investigation.
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Affiliation(s)
- Louis de Mestier
- Department of Gastroenterology and PancreatologyBeaujon Hospital, Paris 7 University, APHP, Clichy, France
| | - Jean-Baptiste Danset
- Department of Hepato-GastroenterologyEuropean Georges-Pompidou Hospital, APHP, Paris, France
| | - Cindy Neuzillet
- Department of Digestive OncologyBeaujon Hospital, Paris 7 University, APHP, Clichy, France
| | - Vinciane Rebours
- Department of Gastroenterology and PancreatologyBeaujon Hospital, Paris 7 University, APHP, Clichy, France
| | - Jérôme Cros
- Department of PathologyBeaujon Hospital, Paris 7 University, APHP, Clichy, France
| | - Nadem Soufir
- Department of GeneticsBichat Hospital, Paris 7 University, APHP, Clichy, France
| | - Pascal Hammel
- Department of Digestive OncologyBeaujon Hospital, Paris 7 University, APHP, Clichy, France
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Mogilyansky E, Clark P, Quann K, Zhou H, Londin E, Jing Y, Rigoutsos I. Post-transcriptional Regulation of BRCA2 through Interactions with miR-19a and miR-19b. Front Genet 2016; 7:143. [PMID: 27630665 PMCID: PMC5005319 DOI: 10.3389/fgene.2016.00143] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 07/21/2016] [Indexed: 12/31/2022] Open
Abstract
Breast cancer type 2, early onset susceptibility gene (BRCA2) is a major component of the homologous recombination DNA repair pathway. It acts as a tumor suppressor whose function is often lost in cancers. Patients with specific mutations in the BRCA2 gene often display discrete clinical, histopathological, and molecular features. However, a subset of sporadic cancers has wild type BRCA2 and display defects in the homology-directed repair pathway, which is the hallmark of ‘BRCAness.’ The mechanisms by which BRCAness arises are not well understood but post-transcriptional regulation of BRCA2 gene expression by microRNAs (miRNAs) may contribute to this phenotype. Here, we examine the post-transcriptional effects that some members of the six-miRNA cluster known as the miR-17/92 cluster have on the abundance of BRCA2’s messenger RNA (mRNA) and protein. We discuss two interactions involving the miR-19a and miR-19b members of the cluster and the 3′UTR of BRCA2’s mRNA. We investigated these miRNA:mRNA interactions in 15 cell lines derived from pancreatic, breast, colon, and kidney tissue. We show that over-expression of these two miRNAs results in a concomitant decrease of BRCA2’s mRNA and protein expression in a subset of the tested cell lines. Additionally, using luciferase reporter assays we identified direct interactions between miR-19a/miR-19b and a miRNA response element (MRE) in BRCA2’s 3′UTR. Our results suggest that BRCA2 is subject to a complex post-transcriptional regulatory program that has specific dependencies on the genetic and phenotypic background of cell types.
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Affiliation(s)
- Elena Mogilyansky
- Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA
| | - Peter Clark
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia PA, USA
| | - Kevin Quann
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA
| | - Honglei Zhou
- Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA
| | - Eric Londin
- Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA
| | - Yi Jing
- Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA
| | - Isidore Rigoutsos
- Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA, USA
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Abstract
Hereditary pancreatic cancer can be diagnosed through family history and/or a personal history of pancreatitis or clinical features suggesting one of the known pancreatic cancer predisposition syndromes. This chapter describes the currently known hereditary pancreatic cancer predisposition syndromes, including Peutz-Jeghers syndrome, familial atypical multiple mole melanoma, hereditary breast and ovarian cancer, Li-Fraumeni syndrome, hereditary non-polyposis colon cancer and familial adenomatous polyposis. Strategies for genetic testing for hereditary pancreatic cancer and the appropriate options for surveillance and cancer risk reduction are discussed. Finally, ongoing research and future directions in the diagnosis and management of hereditary pancreatic cancer will be considered.
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Affiliation(s)
- Jeremy L Humphris
- The Kinghorn Cancer Centre, Cancer Research Program, 370 Victoria St., Darlinghurst, NSW, 2010, Australia.
| | - Andrew V Biankin
- The Kinghorn Cancer Centre, Cancer Research Program, 370 Victoria St., Darlinghurst, NSW, 2010, Australia
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, Bearsden, G61 1BD, United Kingdom
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Norris AL, Roberts NJ, Jones S, Wheelan SJ, Papadopoulos N, Vogelstein B, Kinzler KW, Hruban RH, Klein AP, Eshleman JR. Familial and sporadic pancreatic cancer share the same molecular pathogenesis. Fam Cancer 2015; 14:95-103. [PMID: 25240578 DOI: 10.1007/s10689-014-9755-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is nearly uniformly lethal, with a median overall survival in 2014 of only 6 months. The genetic progression of sporadic PDAC (SPC) is well established, with common somatic alterations in KRAS, p16/CDKN2A, TP53, and SMAD4/DPC4. Up to 10 % of all PDAC cases occur in families with two or more affected first-degree relatives (familial pancreatic cancer, FPC), but these cases do not appear to present at an obviously earlier age of onset. This is unusual because most familial cancer syndrome patients present at a substantially younger age than that of corresponding sporadic cases. Here we collated the reported age of onset for FPC and SPC from the literature. We then used an integrated approach including whole exomic sequencing, whole genome sequencing, RNA sequencing, and high density SNP microarrays to study a cohort of FPC cell lines and corresponding germline samples. We show that the four major SPC driver genes are also consistently altered in FPC and that each of the four detection strategies was able to detect the mutations in these genes, with one exception. We conclude that FPC undergoes a similar somatic molecular pathogenesis as SPC, and that the same gene targets can be used for early detection and minimal residual disease testing in FPC patients.
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Affiliation(s)
- Alexis L Norris
- Department of Pathology, The Sol Goldman Center for Pancreatic Cancer Research, Johns Hopkins University School of Medicine, Room 344, Cancer Research Building-II, 1550 Orleans Street, Baltimore, MD, 21231, USA
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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; 15:1223-31. [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.
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Abstract
Despite decades of scientific and clinical research, pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy. The clinical and pathologic features of PDAC, specifically the known environmental and genetic risk factors, are reviewed here with special emphasis on the hereditary pancreatic cancer (HPC) syndromes. For these latter conditions, strategies are described for their identification, for primary and secondary prevention in unaffected carriers, and for disease management in affected carriers. Nascent steps have been made toward personalized medicine based on the rational use of screening, tumor subtyping, and targeted therapies; these have been guided by growing knowledge of HPC syndromes in PDAC.
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Affiliation(s)
- Ashton A Connor
- Division of General Surgery, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Steven Gallinger
- Division of General Surgery, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
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Holter S, Borgida A, Dodd A, Grant R, Semotiuk K, Hedley D, Dhani N, Narod S, Akbari M, Moore M, Gallinger S. Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma. J Clin Oncol 2015; 33:3124-9. [PMID: 25940717 DOI: 10.1200/jco.2014.59.7401] [Citation(s) in RCA: 299] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
PURPOSE The main purpose of this study was to determine the prevalence of pathogenic BRCA1 and BRCA2 mutations in a consecutively ascertained clinic-based cohort of patients with pancreatic ductal adenocarcinoma and describe the clinical and family history characteristics. PATIENTS AND METHODS Unselected, consecutive, incident patients with pancreatic ductal adenocarcinoma were recruited at a single cancer center over a 2-year period. Participants provided blood for DNA analysis and cancer family history, and cancer treatment records were reviewed. DNA from all patients was analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1 and BRCA2. RESULTS Three hundred six patients were eligible for analysis. Pathogenic germline BRCA mutations were identified in 14 patients (4.6%; 95% CI, 2.2% to 6.9%), including 11 patients with a BRCA2 mutation and three patients with a BRCA1 mutation. Having a cancer family history that met genetic testing criteria of the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care or self-reporting as Ashkenazi Jewish was significantly associated with BRCA mutation carrier status (P=.02, P<.001, and P=.05, respectively). However, the majority of the BRCA mutation-positive patients did not actually meet these genetic testing criteria. CONCLUSION Pathogenic BRCA mutations were identified in 4.6% of a large cohort of clinic-based patients. Considering the implications for family members of BRCA carriers, and possibly tailored chemotherapeutic treatment of patients, our finding has implications for broader BRCA genetic testing for patients with pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Spring Holter
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada
| | - Ayelet Borgida
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada
| | - Anna Dodd
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada
| | - Robert Grant
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada
| | - Kara Semotiuk
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada
| | - David Hedley
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada
| | - Neesha Dhani
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada
| | - Steven Narod
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada
| | - Mohammad Akbari
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada
| | - Malcolm Moore
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada
| | - Steven Gallinger
- Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network; and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada.
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Prakash R, Zhang Y, Feng W, Jasin M. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb Perspect Biol 2015; 7:a016600. [PMID: 25833843 DOI: 10.1101/cshperspect.a016600] [Citation(s) in RCA: 595] [Impact Index Per Article: 59.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks in mammalian cells, the defining step of which is homologous strand exchange directed by the RAD51 protein. The physiological importance of HR is underscored by the observation of genomic instability in HR-deficient cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HR genes. The tumor suppressors BRCA1 and BRCA2, key players at different stages of HR, are frequently mutated in familial breast and ovarian cancers. Other HR proteins, including PALB2 and RAD51 paralogs, have also been identified as tumor suppressors. This review summarizes recent findings on BRCA1, BRCA2, and associated proteins involved in human disease with an emphasis on their molecular roles and interactions.
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Affiliation(s)
- Rohit Prakash
- Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Yu Zhang
- Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Weiran Feng
- Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065
| | - Maria Jasin
- Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065
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Grant RC, Selander I, Connor AA, Selvarajah S, Borgida A, Briollais L, Petersen GM, Lerner-Ellis J, Holter S, Gallinger S. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology 2015; 148:556-64. [PMID: 25479140 PMCID: PMC4339623 DOI: 10.1053/j.gastro.2014.11.042] [Citation(s) in RCA: 233] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 11/20/2014] [Accepted: 11/23/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We investigated the prevalence of germline mutations in APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patients with pancreatic cancer. METHODS The Ontario Pancreas Cancer Study enrolls consenting participants with pancreatic cancer from a province-wide electronic pathology database; 708 probands were enrolled from April 2003 through August 2012. To improve the precision of BRCA2 prevalence estimates, 290 probands were selected from 3 strata, based on family history of breast and/or ovarian cancer, pancreatic cancer, or neither. Germline DNA was analyzed by next-generation sequencing using a custom multiple-gene panel. Mutation prevalence estimates were calculated from the sample for the entire cohort. RESULTS Eleven pathogenic mutations were identified: 3 in ATM, 1 in BRCA1, 2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53. The prevalence of mutations in all 13 genes was 3.8% (95% confidence interval, 2.1%-5.6%). Carrier status was associated significantly with breast cancer in the proband or first-degree relative (P < .01), and with colorectal cancer in the proband or first-degree relative (P < .01), but not family history of pancreatic cancer, age at diagnosis, or stage at diagnosis. Of patients with a personal or family history of breast and colorectal cancer, 10.7% (95% confidence interval, 4.4%-17.0%) and 11.1% (95% confidence interval, 3.0%-19.1%) carried pathogenic mutations, respectively. CONCLUSIONS A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. The heterogeneity of mutations identified in this study shows the value of using a multiple-gene panel in pancreatic cancer.
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Affiliation(s)
- Robert C Grant
- Ontario Institute for Cancer Research, Canada; Department of Medicine, University of Toronto, Canada
| | - Iris Selander
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada
| | - Ashton A Connor
- Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Canada
| | | | - Ayelet Borgida
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada
| | - Laurent Briollais
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada
| | - Gloria M Petersen
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Jordan Lerner-Ellis
- Ontario Institute for Cancer Research, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Canada; Pathology and Laboratory Medicine, Mount Sinai Hospital, Canada
| | - Spring Holter
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada
| | - Steven Gallinger
- Ontario Institute for Cancer Research, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada; Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Canada.
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Chen F, Guo Y, Wang L. The Emerging Genetic Basis and Its Clinical Implication in Pancreatic Cancer. Gastrointest Tumors 2015. [DOI: 10.1159/000435764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
<b><i>Background:</i></b> Pancreatic cancer is one of the most devastating diseases without early detection, effective screening biomarkers and therapeutic treatments. In the past decades, genetic studies have indicated various genes related to this malignancy. <b><i>Summary:</i></b> Genetic alterations have been involved in the initiation, progression and invasion of pancreatic cancer, which might indicate promising targets for early screening, diagnosis and future intervention. Here we will review genetic changes in pancreatic cancer and analyze their correlations with several common precursors and familial syndromes. <b><i>Key Message:</i></b> Genetic analysis for pancreatic cancer or its precursors might help us to characterize patients into subtype individuals in the future and have significant implications for individualized treatments. <b><i>Practical Implications:</i></b> At present, pancreatic cancer is regarded as a disease with a wide range of genetic alterations, including germline and somatic mutations. Some genetic alterations such as <i>KRAS</i>, <i>p16</i><sup><i>CDKN2A</i></sup>, <i>TP53</i> and <i>SMAD4</i> were specifically correlated with different types of histological precursors of pancreatic cancer and some familial syndromes highly related to pancreatic cancer. Moreover, genetic changes also predict drug sensitivity and implicate novel therapeutic targets.
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Abstract
Pancreatic cancer (PC) will affect 48,960 persons in the United States and will result in 40,560 deaths in 2015, according to the American Cancer Society. On a global basis, at least 337,000 persons will be diagnosed with PC. The incidence of PC has increased slightly in the United States, though worldwide cases are likely to increase substantially due to the influence of cigarette smoking, rising obesity and type II diabetes. The development of PC is related to a state of chronic inflammation and insulin resistance. Well-established environmental and personal risk factors for PC include advancing age, cigarette smoking, second-hand tobacco smoke exposure, obesity, inherited familial cancer syndromes, Ashkenazi Jewish heritage, chronic pancreatitis, dietary factors, and diabetes. Other identified associations are human immunodeficiency virus infection, ABO blood group polymorphisms, hepatitis B virus, and Helicobacter pylori.
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Affiliation(s)
- Theresa Pluth Yeo
- Jefferson Pancreas Tumor Registry, Thomas Jefferson University Hospital, Philadelphia, PA.
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Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 2014; 17:70-87. [PMID: 25394175 DOI: 10.1038/gim.2014.147] [Citation(s) in RCA: 388] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 09/12/2014] [Indexed: 12/12/2022] Open
Abstract
DISCLAIMER The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each practice guideline focuses on a clinical or practice-based issue and is the result of a review and analysis of current professional literature believed to be reliable. As such, information and recommendations within the ACMG and NSGC joint practice guidelines reflect the current scientific and clinical knowledge at the time of publication, are current only as of their publication date, and are subject to change without notice as advances emerge. In addition, variations in practice, which take into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments, and/or procedures that differ from the recommendations outlined in this guideline. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. Genetic counseling practice guidelines are never intended to displace a health-care provider's best medical judgment based on the clinical circumstances of a particular patient or patient population. Practice guidelines are published by the ACMG or the NSGC for educational and informational purposes only, and neither the ACMG nor the NSGC "approve" or "endorse" any specific methods, practices, or sources of information.Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome. Yet several patient, clinician, and system-level barriers hinder identification of individuals appropriate for cancer genetics referral. Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. To develop this guideline, a literature search for hereditary cancer susceptibility syndromes was conducted using PubMed. In addition, GeneReviews and the National Comprehensive Cancer Network guidelines were reviewed when applicable. When conflicting guidelines were identified, the evidence was ranked as follows: position papers from national and professional organizations ranked highest, followed by consortium guidelines, and then peer-reviewed publications from single institutions. The criteria for cancer genetic consultation referral are provided in two formats: (i) tables that list the tumor type along with the criteria that, if met, would warrant a referral for a cancer genetic consultation and (ii) an alphabetical list of the syndromes, including a brief summary of each and the rationale for the referral criteria that were selected. Consider referral for a cancer genetic consultation if your patient or any of their first-degree relatives meet any of these referral criteria.
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Affiliation(s)
- Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Robin L Bennett
- Genetic Medicine Clinic, Department of Medicine, University of Washington Medical Center, Seattle, Washington, USA
| | - Adam Buchanan
- Cancer Prevention, Detection and Control Research Program, Duke Cancer Institute, Duke University, Durham, North Carolina, USA
| | - Rachel Pearlman
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Georgia L Wiesner
- Clinical and Translational Hereditary Cancer Program, Division of Genetic Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA
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Golan T, Kanji ZS, Epelbaum R, Devaud N, Dagan E, Holter S, Aderka D, Paluch-Shimon S, Kaufman B, Gershoni-Baruch R, Hedley D, Moore MJ, Friedman E, Gallinger S. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer 2014; 111:1132-8. [PMID: 25072261 PMCID: PMC4453851 DOI: 10.1038/bjc.2014.418] [Citation(s) in RCA: 328] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 06/19/2014] [Accepted: 06/30/2014] [Indexed: 12/12/2022] Open
Abstract
Background: The BRCA1/2 proteins are involved in regulation of cellular proliferation by DNA damage repair via homologous recombination. Therefore, BRCA1/2 mutation carriers with pancreatic cancer may have distinct biologic outcomes. Methods: Patients with BRCA1/2-associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994 and December 2012 were identified from databases at three participating institutions. Clinical data were collected. Disease-free survival and overall survival (OS) were analysed. Results: Overall, 71 patients with PDAC and BRCA1 (n=21), BRCA2 (n=49) or both (n=1) mutations were identified. Mean age at diagnosis was 60.3 years (range 33–83), 81.7% (n=58) had any family history of malignancy; 30% (n=21) underwent primary resection. Out of 71 participants, 12 received experimental therapy; one patient had missing data, these 13 cases were excluded from OS analysis. Median OS for 58 patients was 14 months (95% CI 10–23 months). Median OS for patients with stage 1/2 disease has not been reached with 52% still alive at 60 months. Median OS for stage 3/4 was 12 months (95% CI 6–15). Superior OS was observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies (22 vs 9 months; P=0.039). Conclusion: Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure.
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Affiliation(s)
- T Golan
- 1] The Oncology Institute the Chaim Sheba Medical Center, Tel Hashomer, Israel [2] The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Z S Kanji
- 1] Department of Surgery, University Health Network, Toronto, ON, Canada [2] Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
| | - R Epelbaum
- 1] Department of Oncology, Rambam Health Care Campus, University of Haifa, Haifa, Israel [2] Technion, Faculty of Medicine, Haifa, Israel
| | - N Devaud
- 1] Department of Surgery, University Health Network, Toronto, ON, Canada [2] Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
| | - E Dagan
- 1] Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel [2] Institute of Human Genetics, Rambam Health Care Campus, University of Haifa, Haifa, Israel
| | - S Holter
- 1] Department of Surgery, University Health Network, Toronto, ON, Canada [2] Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
| | - D Aderka
- 1] The Oncology Institute the Chaim Sheba Medical Center, Tel Hashomer, Israel [2] The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - S Paluch-Shimon
- 1] The Oncology Institute the Chaim Sheba Medical Center, Tel Hashomer, Israel [2] The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - B Kaufman
- 1] The Oncology Institute the Chaim Sheba Medical Center, Tel Hashomer, Israel [2] The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - R Gershoni-Baruch
- 1] Technion, Faculty of Medicine, Haifa, Israel [2] Institute of Human Genetics, Rambam Health Care Campus, University of Haifa, Haifa, Israel
| | - D Hedley
- Department of Surgery, University Health Network, Toronto, ON, Canada
| | - M J Moore
- Department of Surgery, University Health Network, Toronto, ON, Canada
| | - E Friedman
- 1] The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel [2] The Susanne Levy Gertner Oncogenetics Unit Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - S Gallinger
- 1] Department of Surgery, University Health Network, Toronto, ON, Canada [2] Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
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Abstract
Pancreatic cancer is one of the most aggressive and intractable human malignant tumors and a leading cause of cancer-related death across the world, with incidence equaling mortality. Because of the extremely high malignance, this disease is usually diagnosed at its advanced stage and recurs even after surgical excision. Pancreatic adenocarcinoma is generally thought to arise from pathological changes of pancreatic duct, and the pancreatic ductal adenocarcinoma accounts for more than 90 % of malignant neoplasms of the pancreas. To date, scientists have revealed several risk factors for pancreatic cancer, including smoking, family history, and aging. However, the underlying molecular mechanism remains unclear. Meanwhile, more mutations of DNA damage response factors have been identified in familial pancreatic cancers, implying a potential link between DNA damage and pancreatic cancer. DNA damage is a recurring phenomenon in our bodies which could be induced by exogenous agents and endogenous metabolism. Accumulated DNA lesions cause genomic instability which eventually results in tumorigenesis. In this study, we showed obvious DNA damages existed in human pancreatic cancer, which activated DNA damage response and the DNA repair pathway including ataxia-telangiectasia mutated, DNA-PK, CHK1, and CHK2. The persistent DNA damage in pancreatic tissue may be the source for its tumorigenesis.
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41
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Familial Pancreatic Cancer: Challenging Diagnostic Approach and Therapeutic Management. J Gastrointest Cancer 2014; 45:256-61. [DOI: 10.1007/s12029-014-9609-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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42
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Chang MC, Wong JM, Chang YT. Screening and early detection of pancreatic cancer in high risk population. World J Gastroenterol 2014; 20:2358-2364. [PMID: 24605033 PMCID: PMC3942839 DOI: 10.3748/wjg.v20.i9.2358] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 01/05/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a serious growing health issue in developed countries. For patients diagnosed with pancreatic cancer, the five year survival rate is below 5%. One major important reason leads to the poor survival rate is lack of early detection of pancreatic cancer. Over 80% of the patients are diagnosed in advanced disease stages. Screening for pancreatic cancer is a desirable option for high risk individuals to allow early detection and treatment of curable pancreatic neoplasms at a pre-invasive stage. This article highlights the need, endpoint, population, method, diagnostic yield, and the problems of current screening programs.
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43
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Reznik R, Hendifar AE, Tuli R. Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma. Front Physiol 2014; 5:87. [PMID: 24624093 PMCID: PMC3939680 DOI: 10.3389/fphys.2014.00087] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 02/13/2014] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided.
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Affiliation(s)
- Robert Reznik
- Department of Radiation Oncology, Cedars-Sinai Medical Center Los Angeles, CA, USA
| | - Andrew E Hendifar
- Department of Radiation Oncology, Cedars-Sinai Medical Center Los Angeles, CA, USA
| | - Richard Tuli
- Department of Radiation Oncology, Cedars-Sinai Medical Center Los Angeles, CA, USA
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44
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Abstract
Beset by poor prognosis, pancreatic ductal adenocarcinoma is classified as familial or sporadic. This review elaborates on the known genetic syndromes that underlie familial pancreatic cancer, where there are opportunities for genetic counseling and testing as well as clinical monitoring of at-risk patients. Such subsets of familial pancreatic cancer involve germline cationic trypsinogen or PRSS1 mutations (hereditary pancreatitis), BRCA2 mutations (usually in association with hereditary breast-ovarian cancer syndrome), CDKN2 mutations (familial atypical mole and multiple melanoma), or DNA repair gene mutations (e.g., ATM and PALB2, apart from those in BRCA2). However, the vast majority of familial pancreatic cancer cases have yet to have their genetic underpinnings elucidated, waiting in part for the results of deep sequencing efforts.
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Affiliation(s)
- Anil K. Rustgi
- Division of Gastroenterology, Department of Medicine and Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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45
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Pancreatic cancer. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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46
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Foulkes WD. BRCA1 and BRCA2 - update and implications on the genetics of breast cancer: a clinical perspective. Clin Genet 2013; 85:1-4. [PMID: 24116874 DOI: 10.1111/cge.12291] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 09/25/2013] [Indexed: 01/16/2023]
Affiliation(s)
- W D Foulkes
- Department of Human Genetics, McGill University, Montreal, QC, Canada
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47
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Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban RH. Recent progress in pancreatic cancer. CA Cancer J Clin 2013; 63:318-48. [PMID: 23856911 PMCID: PMC3769458 DOI: 10.3322/caac.21190] [Citation(s) in RCA: 668] [Impact Index Per Article: 55.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 03/22/2013] [Accepted: 03/22/2013] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in the understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer.
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Affiliation(s)
- Christopher L. Wolfgang
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Joseph M. Herman
- Department of Radiation Oncology & Molecular Radiation Sciences, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Daniel A. Laheru
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Alison P. Klein
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Epidemiology, the Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Michael A. Erdek
- Department of Anesthesiology and Critical Care Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Elliot K. Fishman
- Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Ralph H. Hruban
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
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Meaney-Delman D, Bellcross CA. Hereditary breast/ovarian cancer syndrome: a primer for obstetricians/gynecologists. Obstet Gynecol Clin North Am 2013; 40:475-512. [PMID: 24021253 DOI: 10.1016/j.ogc.2013.05.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
An understanding of the diagnosis and clinical management of hereditary breast and ovarian cancer syndrome (HBOC) is essential for obstetricians/gynecologists. This article provides practical information regarding collecting a family history, cancer risk assessment and genetic testing, BRCA-associated cancer prognosis and treatment, screening recommendations, and prevention strategies. Through appropriate cancer risk assessment, women with BRCA1/2 mutations can be identified, and screening and prevention strategies can be used before a diagnosis of cancer occurs. Women's health providers with a strong working knowledge of HBOC are able to improve the quality of care for women and families impacted by BRCA1/2 mutations.
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Affiliation(s)
- Dana Meaney-Delman
- Department of Gynecology and Obstetrics, Emory University School of Medicine, 49 Jesse Hill Jr Drive, Atlanta, GA 30303, USA.
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49
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Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban RH. Recent progress in pancreatic cancer. CA Cancer J Clin 2013. [PMID: 23856911 DOI: 10.1002/caac.21190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in the understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer.
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Affiliation(s)
- Christopher L Wolfgang
- Associate Professor, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD; Associate Professor, Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD; Associate Professor, Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD
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50
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Lucas AL, Shakya R, Lipsyc MD, Mitchel EB, Kumar S, Hwang C, Deng L, Devoe C, Chabot JA, Szabolcs M, Ludwig T, Chung WK, Frucht H. High prevalence of BRCA1 and BRCA2 germline mutations with loss of heterozygosity in a series of resected pancreatic adenocarcinoma and other neoplastic lesions. Clin Cancer Res 2013; 19:3396-403. [PMID: 23658460 PMCID: PMC3959126 DOI: 10.1158/1078-0432.ccr-12-3020] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is associated with the breast ovarian cancer syndrome (BRCA1/BRCA2) mutations. It is unknown if this association is causal. EXPERIMENTAL DESIGN This is a single-site study of patients who underwent surgical pancreatic tumor resection and self-identified as Ashkenazi Jewish. DNA from normal pancreatic tissue was genotyped for the three Ashkenazi Jewish BRCA1/2 founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, and loss of heterozygosity (LOH) was determined by sequencing DNA from microdissected tumor. When additional tumor tissue was available, p53 immunohistochemistry (IHC) was conducted. RESULTS Thirty-seven patients underwent surgery for PDAC, seven for intraductal papillary mucinous neoplasm (IPMN), and 19 for other diseases. A high prevalence of BRCA1/2 mutations was found in the surgical cohort (12/63; 19.0%; P < 0.001), PDAC cohort (8/37; 21.6%; P < 0.001), and IPMN cohort (2/7; 28.6%; P = .01) compared with published control mutation frequency. A high prevalence of BRCA1 185delAG (8.1%; P < 0.001) and BRCA2 6174delT (10.8%; P < 0.001) in Ashkenazi Jewish patients with PDAC was shown. BRCA1/2 LOH was found in 2 of 4 BRCA1-associated PDACs and 3 of 4 BRCA2-associated PDACs. Positive p53 IHC was found in 5 of 8 BRCA1/2 PDACs. CONCLUSIONS We show a high prevalence of BRCA1/2 mutations with LOH in an Ashkenazi Jewish cohort of surgically resected PDAC and neoplastic lesions, suggesting that these germline mutations are causal in selected individuals.
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Affiliation(s)
- Aimee L Lucas
- Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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