Matthew B Yurgelun1,2, Anu B Chittenden3, Vicente Morales-Oyarvide3, Jonathan A Nowak4,5, Brian M Wolpin3,6, Douglas A Rubinson3,6, Richard F Dunne7, Margaret M Kozak8, Zhi Rong Qian3,4, Marisa W Welch3, Lauren K Brais3, Annacarolina Da Silva3,4, Justin L Bui8, Chen Yuan3,9, Tingting Li4, Wanwan Li4, Atsuhiro Masuda4, Mancang Gu4, Andrea J Bullock10, Daniel T Chang8, Thomas E Clancy11, David C Linehan12, Jennifer J Findeis-Hosey13, Leona A Doyle5, Aaron R Thorner3,14, Matthew D Ducar14, Bruce M Wollison14, Natalia Khalaf6, Kimberly Perez3,6, Sapna Syngal3,6, Andrew J Aguirre6, William C Hahn3,6,14, Matthew L Meyerson3,6,14,15, Charles S Fuchs3,6,16, Shuji Ogino3,4,9,5, Jason L Hornick5, Aram F Hezel7, Albert C Koong8,17. 1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. matthew_yurgelun@dfci.harvard.edu. 2. Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA. matthew_yurgelun@dfci.harvard.edu. 3. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. 4. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. 5. Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. 6. Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA. 7. Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. 8. Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, USA. 9. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 10. Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. 11. Department of Surgery, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. 12. Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA. 13. Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA. 14. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA. 15. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. 16. Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. 17. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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.
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.
Entities:
Keywords:
Familial pancreatic cancer; Hereditary breast and ovarian cancer; Lynch syndrome; PARP inhibitors
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