The prevalence of hereditary pancreatitis mutations in families with pancreatic cancer.

Abstract

e15728 Background: Germline pathogenic variants (PV) in hereditary cancer risk genes are found in ~10-15% of pancreatic adenocarcinomas/cancers (PC), but most cases of familial PC have no identifiable genetic cause. Chronic pancreatitis is an established risk factor for PC, with a lifetime risk of PC of 10-30%, and has been associated with germline mutations in several genes: PRSS1, SPINK1, CASR, CTRC, and CFTR. Few studies have examined the prevalence of PV in the pancreatitis risk genes among patients reporting a personal or family history (FHx) of PC. Methods: The FCCC Risk Assessment Program (RAP) database was queried to identify patients tested for PRSS1, SPINK1, CASR, CTRC, and CFTR as part of risk assessment. Pedigrees, demographic and cancer history data were reviewed. De-identified data from Invitae on patients found to be CFTR+ on hereditary pancreatitis testing were also reviewed for personal/FHx of PC. Results: 26 patients with PC and 48 patients with a FHx of PC underwent germline testing for the pancreatitis genes at FCCC. 7 of 26 (26.9%) patients with PC carried at least one CFTR mutation, while 3 of 48 (6.3%) patients with a FHx of PC carried a CFTR mutation. Interestingly, 8 patients carried an intronic variant in the CFTR gene. No patients with PC and 2 of 48 (4.2%) patients with a FHx of PC carried a SPINK1 mutation. The CFTR mutation rate in PC patients exceeded the expected carrier rate (2.6-3.6%)(p < 0.001). The SPINK1 mutation rate in PC patients also exceeded the expected carrier rate but was not statistically significant (1.9%)(p = 0.23). CaSR, PRSS1, and CTRC mutations were not identified in our population. Personal/FHx data were available to review for 175 of the 496 CFTR+ patients tested through Invitae. 49 of 175 (28%) had a personal history of PC and 105 of 175 (60%) had a reported FHx of PC. Strikingly, 23% of CFTR+ patients carried pathogenic mutations in other genes (most commonly SPINK1). Conclusions: In our select sample, CFTR mutations, and in particular a known intronic variant, were highly enriched in a population of patients undergoing risk assessment for hereditary PC. Commercial data suggest a substantial minority of CFTR+ carriers with a personal/FHx of PC may also carry SPINK1 mutations.