Germline Variants in Chronic Pancreatitis-Associated Genes and Risk of Pancreatic Ductal Adenocarcinoma

Hereditary chronic pancreatitis (CP) is associated with elevated risk of pancreatic ductal adenocarcinoma (PDAC), but the specific contributing genes and their associated risk magnitudes remain incompletely defined. We aimed to investigate whether pathogenic germline variants (PGVs) in all 11 known CP-associated genes (CASR, CEL, CFTR, CLDN2, CPA1, CPB1, CTRC, PNLIP, PRSS1, SPINK1, TRPV6) predispose to PDAC and to quantify their risk estimates.

Germline whole-exome sequencing was performed among 4528 PDAC cases and 52,659 controls without PDAC. Gene-based burden analyses were performed to identify PDAC-associated genes, followed by variant-level analyses of significant genes to determine the primary contributors to the gene-level associations. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression, adjusting for age, sex, and ancestry principal components.

PRSS1 (P < .001) and CFTR (P = .008) were associated with PDAC risk. The PRSS1 association was driven primarily by the p.Arg122His variant, which was associated with markedly elevated risk (OR, 72.34; P < .001). Six CFTR variants were significantly associated with PDAC, 5 of which had risk estimates (OR) ranging from 3.66 to 10.21. Most PDAC cases carrying CFTR variants lacked clinically diagnosed CP, whereas most PRSS1 variant carriers did not have a family history of PDAC.

Among CP-associated genes, rare PGVs in PRSS1 and CFTR are associated with PDAC risk. The PRSS1 signal was driven mainly by p.Arg122His, whereas the CFTR association involved 6 variants, with 5 having clinically relevant risk magnitudes. If confirmed in larger studies, these findings could help inform germline testing strategies in patients with PDAC.