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Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer

Educational Objective
To learn whether cancer predisposition genes are associated with increased risk of pancreatic cancer.
1 Credit CME
Key Points

Question  Are there germline mutations in cancer predisposition that are associated with pancreatic cancer?

Findings  In a case-control study that included 3030 patients with pancreatic cancer and 123 136 reference controls, 6 genes were independently associated with pancreatic cancer, with odds ratios between 2.58 and 12.33 after correction for multiple comparisons. In aggregate, these genes were observed in 5.5% of patients with pancreatic cancer.

Meaning  Six genes were identified that were associated with pancreatic cancer; further research is needed for replication in other populations.

Abstract

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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Article Information

Corresponding Author: Fergus J. Couch, PhD, Department of Laboratory Medicine and Pathology, Mayo Clinic, Stabile 2-42, 200 First St SW, Rochester, MN 55905 (couch.fergus@mayo.edu).

Accepted for Publication: May 16, 2018.

Author Contributions: Drs Petersen and Couch had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Petersen and Couch contributed equally to this study.

Concept and design: Polley, Bamlet, Samara, McWilliams, Petersen, Couch.

Acquisition, analysis, or interpretation of data: Hu, Hart, Polley, Gnanaolivu, Shimelis, Lee, Lilyquist, Na, Moore, Antwi, Bamlet, Chaffee, DiCarlo, Wu, Kasi, McWilliams, Petersen, Couch.

Drafting of the manuscript: Hu, Hart, Shimelis, Na, Moore, Bamlet, Chaffee, Kasi, Petersen, Couch.

Critical revision of the manuscript for important intellectual content: Hu, Hart, Polley, Gnanaolivu, Shimelis, Lee, Lilyquist, Antwi, Bamlet, DiCarlo, Wu, Samara, Kasi, McWilliams, Petersen.

Statistical analysis: Hu, Hart, Polley, Gnanaolivu, Shimelis, Na, Moore, Bamlet, Couch.

Obtained funding: McWilliams, Petersen, Couch.

Administrative, technical, or material support: Lee, Chaffee, DiCarlo, Wu, Samara, Petersen, Couch.

Supervision: Petersen, Couch.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Wu, DiCarlo, and Samara are employees of Qiagen Inc. Dr McWilliams reports advisory board membership for Bristol-Myers Squibb, Ipsen, and Merrimack. No other disclosures were reported.

Funding/Support: The study was funded by National Institutes of Health grants R01CA192393 and R01CA97075, the Mayo Clinic Specialized Program of Research Excellence in Pancreatic Cancer (grant P50CA102701), the Mayo Clinic Department of Laboratory Medicine and Pathology Research Funds, the Mayo Clinic Center for Individualized Medicine, the Rolfe Pancreatic Cancer Foundation, and the Vernon F. and Mae E. Thompson Charitable Fund.

Role of the Funder/Sponsor: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Previous Presentation: This study was presented in part at the American Society for Human Genetics annual meeting; October 17-21, 2017; Orlando, Florida.

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