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Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) inWe 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 (In RVA tests,These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in

PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A. 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 ( CDKN2A +) and without ( CDKN2A–) GPV. Exome sequencing was performed on 84 patients with PDAC, 47 CDKN2A+ and 37 CDKN2A–. After variant filtering, various RVA tests and permutation tests were run separately by CDKN2A 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, ERCC4 and RET showed the most compelling evidence as plausible PDAC candidate genes for CDKN2A+ patients. In contrast, the findings in CDKN2A– patients provided evidence for HMBS, EPCAM, and MRE11 as potential new candidate genes and confirmed ATM, BRCA2, and PALB2 as PDAC genes, consistent with findings in The Cancer Genome Atlas and the UKB. As expected, CDKN2A– 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 CDKN2A. CONCLUSION These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in CDKN2A+ patients has a distinct etiology from PDAC in CDKN2A– patients.