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Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.
Yurgelun, Matthew B; Chittenden, Anu B; Morales-Oyarvide, Vicente; Rubinson, Douglas A; Dunne, Richard F; Kozak, Margaret M; Qian, Zhi Rong; Welch, Marisa W; Brais, Lauren K; Da Silva, Annacarolina; Bui, Justin L; Yuan, Chen; Li, Tingting; Li, Wanwan; Masuda, Atsuhiro; Gu, Mancang; Bullock, Andrea J; Chang, Daniel T; Clancy, Thomas E; Linehan, David C; Findeis-Hosey, Jennifer J; Doyle, Leona A; Thorner, Aaron R; Ducar, Matthew D; Wollison, Bruce M; Khalaf, Natalia; Perez, Kimberly; Syngal, Sapna; Aguirre, Andrew J; Hahn, William C; Meyerson, Matthew L; Fuchs, Charles S; Ogino, Shuji; Hornick, Jason L; Hezel, Aram F; Koong, Albert C; Nowak, Jonathan A; Wolpin, Brian M.
Affiliation
  • Yurgelun MB; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. matthew_yurgelun@dfci.harvard.edu.
  • Chittenden AB; Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA. matthew_yurgelun@dfci.harvard.edu.
  • Morales-Oyarvide V; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Rubinson DA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Dunne RF; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Kozak MM; Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA.
  • Qian ZR; Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
  • Welch MW; Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, USA.
  • Brais LK; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Da Silva A; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Bui JL; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Yuan C; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Li T; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Li W; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Masuda A; Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, USA.
  • Gu M; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Bullock AJ; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Chang DT; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Clancy TE; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Linehan DC; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Findeis-Hosey JJ; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Doyle LA; Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • Thorner AR; Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, USA.
  • Ducar MD; Department of Surgery, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Wollison BM; Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA.
  • Khalaf N; Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.
  • Perez K; Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Syngal S; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Aguirre AJ; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Hahn WC; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Meyerson ML; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Fuchs CS; Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA.
  • Ogino S; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Hornick JL; Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA.
  • Hezel AF; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Koong AC; Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA.
  • Nowak JA; Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA.
  • Wolpin BM; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Genet Med ; 21(1): 213-223, 2019 01.
Article in En | MEDLINE | ID: mdl-29961768
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.
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Full text: 1 Database: MEDLINE Main subject: Pancreatic Neoplasms / Adenocarcinoma / Genetic Predisposition to Disease / Neoplasm Proteins Type of study: Prognostic_studies / Risk_factors_studies Limits: Adult / Aged / Female / Humans / Male / Middle aged Language: En Journal: Genet Med Journal subject: GENETICA MEDICA Year: 2019 Type: Article Affiliation country: United States
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Full text: 1 Database: MEDLINE Main subject: Pancreatic Neoplasms / Adenocarcinoma / Genetic Predisposition to Disease / Neoplasm Proteins Type of study: Prognostic_studies / Risk_factors_studies Limits: Adult / Aged / Female / Humans / Male / Middle aged Language: En Journal: Genet Med Journal subject: GENETICA MEDICA Year: 2019 Type: Article Affiliation country: United States