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

Matthew B. Yurgelun; Anu B. Chittenden; Vicente Morales-Oyarvide; Douglas A. Rubinson; Richard F. Dunne; Margaret M. Kozak; Zhi Rong Qian; Marisa W. Welch; Lauren K. Brais; Annacarolina Da Silva; Justin L. Bui; Chen Yuan; Tingting Li; Wanwan Li; Atsuhiro Masuda; Mancang Gu; Andrea J. Bullock; Daniel T. Chang; Thomas E. Clancy; David C. Linehan; Jennifer J. Findeis-Hosey; Leona A. Doyle; Aaron R. Thorner; Matthew D. Ducar; Bruce M. Wollison; Natalia Khalaf; Kimberly Perez; Sapna Syngal; Andrew J. Aguirre; William C. Hahn; Matthew L. Meyerson; Charles S. Fuchs; Shuji Ogino; Jason L. Hornick; Aram F. Hezel; Albert C. Koong; Jonathan A. Nowak; Brian M. Wolpin

doi:10.1038/s41436-018-0009-5

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

Journal article

Open access

Peer reviewed

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

Matthew B. Yurgelun, Anu B. Chittenden, Vicente Morales-Oyarvide, Douglas A. Rubinson, Richard F. Dunne, Margaret M. Kozak, Zhi Rong Qian, Marisa W. Welch, Lauren K. Brais, Annacarolina Da Silva, …

Genetics in medicine, Vol.21(1), pp.213-223

01/2019

DOI: 10.1038/s41436-018-0009-5

PMCID: PMC6666401

PMID: 29961768

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Abstract

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.

Familial pancreatic cancer

Hereditary breast and ovarian cancer

Lynch syndrome

PARP inhibitors

Details

Title: Subtitle: Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer
Creators: Matthew B. Yurgelun - Dana-Farber Cancer Institute
Anu B. Chittenden - Dana-Farber Cancer Institute
Vicente Morales-Oyarvide - Dana-Farber Cancer Institute
Douglas A. Rubinson - Dana-Farber Cancer Institute
Richard F. Dunne - University of Rochester Medical Center
Margaret M. Kozak - Stanford University
Zhi Rong Qian - Dana-Farber Cancer Institute
Marisa W. Welch - Dana-Farber Cancer Institute
Lauren K. Brais - Dana-Farber Cancer Institute
Annacarolina Da Silva - Dana-Farber Cancer Institute
Justin L. Bui - Stanford University
Chen Yuan - Dana-Farber Cancer Institute
Tingting Li - Dana-Farber Cancer Institute
Wanwan Li - Dana-Farber Cancer Institute
Atsuhiro Masuda - Dana-Farber Cancer Institute
Mancang Gu - Dana-Farber Cancer Institute
Andrea J. Bullock - Beth Israel Deaconess Medical Center
Daniel T. Chang - Stanford University
Thomas E. Clancy - Brigham and Women's Hospital
David C. Linehan - University of Rochester Medical Center
Jennifer J. Findeis-Hosey - University of Rochester Medical Center
Leona A. Doyle - Brigham and Women's Hospital
Aaron R. Thorner - Dana-Farber Cancer Institute
Matthew D. Ducar - Dana-Farber Cancer Institute
Bruce M. Wollison - Dana-Farber Cancer Institute
Natalia Khalaf - Brigham and Women's Hospital
Kimberly Perez - Dana-Farber Cancer Institute
Sapna Syngal - Dana-Farber Cancer Institute
Andrew J. Aguirre - Brigham and Women's Hospital
William C. Hahn - Dana-Farber Cancer Institute
Matthew L. Meyerson - Dana-Farber Cancer Institute
Charles S. Fuchs - Dana-Farber Cancer Institute
Shuji Ogino - Dana-Farber Cancer Institute
Jason L. Hornick - Brigham and Women's Hospital
Aram F. Hezel - University of Rochester Medical Center
Albert C. Koong - Department of Radiation Oncology, Stanford Cancer Institute, Stanford, USA
Jonathan A. Nowak - Dana-Farber Cancer Institute
Brian M. Wolpin - Dana-Farber Cancer Institute
Resource Type: Journal article
Publication Details: Genetics in medicine, Vol.21(1), pp.213-223
Publisher: Elsevier Inc
DOI: 10.1038/s41436-018-0009-5
PMID: 29961768
PMCID: PMC6666401
ISSN: 1098-3600
eISSN: 1530-0366
Language: English
Date published: 01/2019
Academic Unit: Radiation Oncology
Record Identifier: 9984313090802771

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