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Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer
Open accessPublished version of a preprint
Abstract
Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types. Significance: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer. Cancer Discov; 6(2); 166–75. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109
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“Deleterious variants in the known pancreatic cancer susceptibility genes account for ~10–20% of the familial clustering of pancreatic cancer.”
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“Pancreatic surveillance is recommended for carriers of germline deleterious variants in cancer susceptibility gene,22–26: BRCA2, ATM, BRCA1, PALB2, CDKN2A, STK11, MLH1 and MSH2.”
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“Our data show, for the first time, that predisposition to MPM is very heterogeneous, similar to that reported for pancreatic cancer and other cancer types [17,18,38].”
From Germline Mutations in DNA Repair Genes Predispose Asbestos-Exposed Patients to Malignant Pleural Mesothelioma (2017) · cites this paper as [18]
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Metadata
- Authors
- Roberts, N. J., Norris, A. L., Petersen, G. M., Bondy, M. L., Brand, R., Gallinger, S., Kurtz, R. C., Olson, S. H., Rustgi, A. K., Schwartz, A. G., Stoffel, E., Syngal, S., Zogopoulos, G., Ali, S. Z., Axilbund, J., Chaffee, K. G., Chen, Y.-C., Cote, M. L., Childs, E. J., Douville, C., Goes, F. S., Herman, J. M., Iacobuzio-Donahue, C., Kramer, M., Makohon-Moore, A., McCombie, R. W., McMahon, K. W., Niknafs, N., Parla, J., Pirooznia, M., Potash, J. B., Rhim, A. D., Smith, A. L., Wang, Y., Wolfgang, C. L., Wood, L. D., Zandi, P. P., Goggins, M., Karchin, R., Eshleman, J. R., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Hruban, R. H., & Klein, A. P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Mayo Clinic (US)
- Baylor College of Medicine (US)
- University of Pittsburgh (US)
- 6Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
- Memorial Sloan Kettering Cancer Center (US)
- Abramson Cancer Center (US)
- Wayne State University (US)
- University of Michigan (US)
- Brigham and Women's Hospital (US)
- Research Institute of the McGill University Health Centre (CA)
- 3Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
- 15Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
- 10Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
- 19Memorial Sloan Kettering Cancer Center, New York, New York.
- Cold Spring Harbor Laboratory (US)
- 20Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
- University of Iowa (US)
- Corresponding author
- Roberts, Nicholas J.
- Kinzler, Kenneth W.
- Vogelstein, Bert
- Hruban, Ralph H.
- Klein, Alison P.
- ORCID
- Roberts, Nicholas J.
- Norris, Alexis L.
- Petersen, Gloria M.
- Bondy, Melissa L.
- Brand, Randall
- Kurtz, Robert C.
- Olson, Sara H.
- Rustgi, Anil K.
- Schwartz, Ann G.
- Stoffel, Elena
- Syngal, Sapna
- Zogopoulos, George
- Ali, Syed Z.
- Douville, Christopher
- Goes, Fernando S.
- Herman, Joseph M.
- Kramer, Melissa
- Makohon-Moore, Alvin
- Niknafs, Noushin
- Pirooznia, Mehdi
- Potash, James B.
- Rhim, Andrew D.
- Smith, Alyssa L.
- Wang, Yuxuan
- Wolfgang, Christopher L.
- Wood, Laura D.
- Zandi, Peter P.
- Goggins, Michael
- Karchin, Rachel
- Eshleman, James R.
- Papadopoulos, Nickolas
- Kinzler, Kenneth W.
- Vogelstein, Bert
- Hruban, Ralph H.
- Klein, Alison P.
- Venue
- Cancer Discovery
- Published
- 2016-02-01
- Volume
- 6
- Issue
- 2
- Pages
- 166-175
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4744563
- OpenAlex
- W2232697670
- Cited by
- 361
- References
- 49
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 42 · 2023: 33 · 2022: 30 · 2021: 58 · 2020: 41 · 2019: 43 · 2018: 35 · 2017: 32 · 2016: 18
- FWCI
- 12.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (UL1TR000371, 5p30ca045508-35)
- National Institute of Mental Health (R01MH087979, K01MH093809)
- National Cancer Institute (K99CA190889, R01CA-97075, R01-CA57345, R01CA154823, R00CA190889, R37CA043460, P50CA102701, R01CA057345, P30-CA045508, R01CA097075, R01CA177857, P50CA062924, R37CA057345, P30CA008748, P30CA015083, P30CA006973)
- National Institute of General Medical Sciences (T32GM007309, T32GM007057, T32GM008752)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK060694)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- familial pancreatic cancer, pancreatic ductal adenocarcinoma, germline mutations, cancer susceptibility genes, BRCA2, CDKN2A, ATM, somatic mutations, hematopoietic cells, genetic heterogeneity, hereditary cancer predisposition, rare deleterious variants
- MeSH terms
- Carcinoma, Humans, Pancreatic Neoplasms, Point Mutation, Sequence Analysis, DNA, Germ-Line Mutation, Cyclin-Dependent Kinase Inhibitor p16, Genetic Predisposition to Disease, BRCA2 Protein, Ataxia Telangiectasia Mutated Proteins
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