Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in <i>CDKN2A</i> and Pancreatic Cancer.

Abstract

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