Summary: | Multigene germline panel testing is recommended for Pancreatic Cancer (PC) patients; however, for non-<i>BRCA1/2</i> 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 <i>BRCA1/2</i> (4.5%, all <70 y), <i>CDKN2A</i> (4.5%, all >50 y), ATM (2.1%). PV carriers were younger (64 vs. 67; <i>p</i> = 0.02) and had more frequent personal/FH of PC, melanoma and breast/ovarian cancer (all <i>p</i> < 0.05). The Overall Survival (OS) was longer in patients carrying PVs (HR 0.78; <i>p</i> = 0.090), comprising <i>ATM</i> carriers (HR 0.33; <i>p</i> = 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. <i>ATM</i> PVs were positively associated with OS in 41% of PV carriers, 60% of whom carried <i>CDKN2A,</i><i>BRCA2</i> or <i>ATM</i> PVs, had negative FH and would have been missed by traditional referral. Thus, <i>CDKN2A</i> and <i>ATM</i> should be added to <i>BRCA1/2</i> testing regardless of FH.
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