Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in and Pancreatic Cancer.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in . However, it is unclear what role this gene or other genes play in its etiology.

Materials And Methods: We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with () and without () GPV. Exome sequencing was performed on 84 patients with PDAC, 47 and 37 . After variant filtering, various RVA tests and permutation tests were run separately by status. Genes with the strongest nominal associations were evaluated in patients with PDAC from The Cancer Genome Atlas and the UK Biobank (UKB). A secondary analysis including only GPV from UKB was also performed.

Results: In RVA tests, and showed the most compelling evidence as plausible PDAC candidate genes for patients. In contrast, the findings in patients provided evidence for , , and as potential new candidate genes and confirmed , and as PDAC genes, consistent with findings in The Cancer Genome Atlas and the UKB. As expected, patients were more likely to harbor GPVs from the 189 genes investigated. When including only GPVs from UKB, significant associations with PDAC were seen for ATM, BRCA2, and .

Conclusion: These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in patients has a distinct etiology from PDAC in patients.