Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer
Open accessAbstract
Importance: Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined. Objective: To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer. Design, Setting, and Participants: Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in a Mayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database. Exposures: Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer. Main Outcomes and Measures: Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction-based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls. Results: Comparing 3030 case patients with pancreatic cancer (43.2% female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 [SD, 10.7] years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3% of cases and 0.02% of controls; odds ratio [OR], 12.33; 95% CI, 5.43-25.61); TP53 (0.2% of cases and 0.02% of controls; OR, 6.70; 95% CI, 2.52-14.95); MLH1 (0.13% of cases and 0.02% of controls; OR, 6.66; 95% CI, 1.94-17.53); BRCA2 (1.9% of cases and 0.3% of controls; OR, 6.20; 95% CI, 4.62-8.17); ATM (2.3% of cases and 0.37% of controls; OR, 5.71; 95% CI, 4.38-7.33); and BRCA1 (0.6% of cases and 0.2% of controls; OR, 2.58; 95% CI, 1.54-4.05). Conclusions and Relevance: In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5% of all pancreatic cancer patients, including 7.9% of patients with a family history of pancreatic cancer and 5.2% of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.
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The risk of PDAC increases with the number of affected first-degree relatives with pancreatic cancer and in those who carry a pathogenic germline variant in a pancreatic cancer susceptibility gene.
“The risk increases with the number of affected first-degree relatives with pancreatic cancer and in those who carry a pathogenic germline variant in a pancreatic cancer susceptibility gene.9-11”
From The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival (2022) · cites this paper as [11]
Deleterious variants have been reported in about 5-10% of patients with apparently sporadic pancreatic cancer.
“Deleterious variants have also been reported in ~5–10% of patients with apparently sporadic pancreatic cancer.”
Mutation carriers who develop pancreatic cancer are diagnosed at a slightly younger age, about 3-5 years, than those with sporadic forms of the disease.
“mutation carriers who develop pancreatic cancer are diagnosed at a slightly younger age (~3–5 years) than those with sporadic forms of the disease.”
The absence of a family history in individuals carrying the same specific mutations indicates that these mutations are context-specific.
“However, the absence of a family history in individuals with the same specific mutations indicates that these mutations are context-specific.29”
From Early detection of pancreatic cancer (2020) · cites this paper as [29]
Mutations associated with pancreatic ductal adenocarcinoma are almost as frequent in sporadic disease as in individuals with a family history.
“the mutations are almost as frequent in sporadic disease as in individuals with a family history.29”
From Early detection of pancreatic cancer (2020) · cites this paper as [29]
Families with a strong history of pancreatic ductal adenocarcinoma mostly do not have mutations in the genes known to be associated with the disease.
“families with a strong history of pancreatic ductal adenocarcinoma mostly do not have mutations in the genes known to be associated with the disease.26,27,29,30”
From Early detection of pancreatic cancer (2020) · cites this paper as [29]
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- Authors
- Hu, C., Hart, S. N., Polley, E. C., Gnanaolivu, R., Shimelis, H., Lee, K. Y., Lilyquist, J., Na, J., Moore, R., Antwi, S. O., Bamlet, W. R., Chaffee, K. G., DiCarlo, J., Wu, Z., Samara, R., Kasi, P. M., McWilliams, R. R., Petersen, G. M., & Couch, F. J.
- Affiliations
- Mayo Clinic (US)
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
- Qiagen (Germany) (DE)
- Corresponding author
- Couch, Fergus J.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2018-06-19
- Volume
- 319
- Issue
- 23
- Pages
- 2401
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC6092184
- OpenAlex
- W2809494794
- Cited by
- 577
- References
- 45
- Citations by year
- 2026: 46 · 2025: 64 · 2024: 66 · 2023: 84 · 2022: 88 · 2021: 96 · 2020: 59 · 2019: 59 · 2018: 14 · 2017: 1
- FWCI
- 21.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Rolfe Pancreatic Cancer Foundation
- National Institutes of Health
- Center for Individualized Medicine, Mayo Clinic
- National Cancer Institute (R25CA092049, R01CA192393, P50CA102701, R01CA097075)
- 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
- pancreatic cancer, germline mutations, cancer susceptibility genes, CDKN2A, TP53, MLH1, BRCA2, PALB2, ATM, PMS2, PMS1, FANCM, FANCL, FANCD2, FANCG, FAN1
- MeSH terms
- Aged, DNA, Neoplasm, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms, Registries, Risk, Proportional Hazards Models, Survival Analysis, Case-Control Studies, Sequence Analysis, DNA, Germ-Line Mutation, Genetic Predisposition to Disease, Carcinoma, Pancreatic Ductal, Databases, Genetic
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