Germline cancer susceptibility gene variants,somatic second hits,and survival outcomes in patients with resected pancreatic cancer |
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| Institution: | 1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA;2. Department of Medicine, Brigham & Women’s Hospital, Boston, MA, USA;3. Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA;4. Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, USA;5. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA;6. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA;7. Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA;8. Department of Surgery, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA;9. Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA;10. Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA;11. Department of Pathology, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA;12. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA;13. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA;14. Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA;15. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA |
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| Abstract: | PurposeGermline 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.MethodsUsing 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.ResultsWe 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).ConclusionNearly 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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