Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.

Yurgelun MB1,2, Chittenden AB3, Morales-Oyarvide V3, Rubinson DA3,4, Dunne RF5, Kozak MM6, Qian ZR3,7, Welch MW3, Brais LK3, Da Silva A3,7, Bui JL6, Yuan C3,8, Li T7, Li W7, Masuda A7, Gu M7, Bullock AJ9, Chang DT6, Clancy TE10, Linehan DC11, Findeis-Hosey JJ12, Doyle LA13, Thorner AR3,14, Ducar MD14, Wollison BM14, Khalaf N4, Perez K3,4, Syngal S3,4, Aguirre AJ4, Hahn WC3,4,14, Meyerson ML3,4,14,15, Fuchs CS3,4,16, Ogino S3,7,8,13, Hornick JL13, Hezel AF5, Koong AC6,17, Nowak JA7,13, Wolpin BM3,4.

Author information

Abstract

PURPOSE:

Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses.

METHODS:

Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression.

RESULTS:

We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05).

CONCLUSION:

Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.