Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer GENETICS IN MEDICINE Yurgelun, M. B., Chittenden, A. B., Morales-Oyarvide, V., Rubinson, D. A., Dunne, R. F., Kozak, M. M., Qian, Z., Welch, M. W., Brais, L. K., Da Silva, A., Bui, J. L., Yuan, C., Li, T., Li, W., Masuda, A., Gu, M., Bullock, A. J., Chang, D. T., Clancy, T. E., Linehan, D. C., Findeis-Hosey, J. J., Doyle, L. A., Thorner, A. R., Ducar, M. D., Wollison, B. M., Khalaf, N., Perez, K., Syngal, S., Aguirre, A. J., Hahn, W. C., Meyerson, M. L., Fuchs, C. S., Ogino, S., Hornick, J. L., Hezel, A. F., Koong, A. C., Nowak, J. A., Wolpin, B. M. 2019; 21 (1): 213–23


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

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