Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients

SIMPLE SUMMARY: Multigene germline panel testing data, extended beyond BRCA, in unselected pancreatic cancer patients, are missing in the Italian population. We aimed here to determine the prevalence and impact of pathogenic variants in 51 pancreatic cancer candidate susceptibility genes in an unselected cohort of Italian pancreatic cancer patients. We found that 17% were carriers. CDKN2A was the most frequently mutated gene, followed by BRCA2 and ATM. Carriers showed better overall survival. A total of 41% of them had no family history. All CDKN2A carriers were older than 50 years, and BRCA1/2 carriers were younger than 70 years. CDKN2A and ATM should be added to current BRCA1/2 testing independently of family history in our population. ABSTRACT: Multigene germline panel testing is recommended for Pancreatic Cancer (PC) patients; however, for non-BRCA1/2 genes, the clinical utility is unclear. A comprehensive multi-gene assessment in unselected Italian PC patients is missing. We evaluated the prevalence and impact of Pathogenic Variants (PV) in 51 PC susceptibility genes in a real-world series of 422 Italian PC patients unselected for Family History (FH), compared the clinical characteristics and conducted survival analyses. 17% of patients had PVs (70/422), mainly in BRCA1/2 (4.5%, all <70 y), CDKN2A (4.5%, all >50 y), ATM (2.1%). PV carriers were younger (64 vs. 67; p = 0.02) and had more frequent personal/FH of PC, melanoma and breast/ovarian cancer (all p < 0.05). The Overall Survival (OS) was longer in patients carrying PVs (HR 0.78; p = 0.090), comprising ATM carriers (HR 0.33; p = 0.054). In the oxaliplatin-treated subset, PV carriers showed better control of the disease, although this was not statistically significant (67% vs. 56%). CDKN2A, BRCA2 and ATM were the most frequently altered genes. ATM PVs were positively associated with OS in 41% of PV carriers, 60% of whom carried CDKN2A, BRCA2 or ATM PVs, had negative FH and would have been missed by traditional referral. Thus, CDKN2A and ATM should be added to BRCA1/2 testing regardless of FH.