Subjects

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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Author information

Author notes

  1. These authors contributed equally: Matthew B. Yurgelun, Anu B. Chittenden, Vicente Morales-Oyarvide, Jonathan A. Nowak, Brian M. Wolpin.

  2. Dr. Yurgelun, Ms. Chittenden, and Dr. Morales-Oyarvide are co-first authors and contributed equally to one another. Drs. Nowak and Wolpin are co-senior authors and contributed equally to one another.

Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    • Matthew B. Yurgelun MD
    • , Anu B. Chittenden MS, CGC
    • , Vicente Morales-Oyarvide MD, MPH
    • , Douglas A. Rubinson MD, PhD
    • , Zhi Rong Qian MD, PhD
    • , Marisa W. Welch BA
    • , Lauren K. Brais MPH
    • , Annacarolina Da Silva MD
    • , Chen Yuan MS
    • , Aaron R. Thorner PhD
    • , Kimberly Perez MD
    • , Sapna Syngal MD, MPH
    • , William C. Hahn MD, PhD
    • , Matthew L. Meyerson MD, PhD
    • , Charles S. Fuchs MD, MPH
    • , Shuji Ogino MD, PhD
    •  & Brian M. Wolpin MD, MPH
  2. Department of Medicine, Brigham & Women’s Hospital, Boston, MA, USA

    • Matthew B. Yurgelun MD
    • , Douglas A. Rubinson MD, PhD
    • , Natalia Khalaf MD
    • , Kimberly Perez MD
    • , Sapna Syngal MD, MPH
    • , Andrew J. Aguirre MD, PhD
    • , William C. Hahn MD, PhD
    • , Matthew L. Meyerson MD, PhD
    • , Charles S. Fuchs MD, MPH
    •  & Brian M. Wolpin MD, MPH
  3. Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA

    • Richard F. Dunne MD
    •  & Aram F. Hezel MD
  4. Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, USA

    • Margaret M. Kozak MD
    • , Justin L. Bui BS
    • , Daniel T. Chang MD
    •  & Albert C. Koong MD, PhD
  5. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Zhi Rong Qian MD, PhD
    • , Annacarolina Da Silva MD
    • , Tingting Li MD, PhD
    • , Wanwan Li MD
    • , Atsuhiro Masuda MD, PhD
    • , Mancang Gu PhD
    • , Shuji Ogino MD, PhD
    •  & Jonathan A. Nowak MD, PhD
  6. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Chen Yuan MS
    •  & Shuji Ogino MD, PhD
  7. Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    • Andrea J. Bullock MD
  8. Department of Surgery, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • Thomas E. Clancy MD
  9. Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA

    • David C. Linehan MD
  10. Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA

    • Jennifer J. Findeis-Hosey MD
  11. Department of Pathology, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • Leona A. Doyle MD
    • , Shuji Ogino MD, PhD
    • , Jason L. Hornick MD, PhD
    •  & Jonathan A. Nowak MD, PhD
  12. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA

    • Aaron R. Thorner PhD
    • , Matthew D. Ducar MS
    • , Bruce M. Wollison
    • , William C. Hahn MD, PhD
    •  & Matthew L. Meyerson MD, PhD
  13. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA

    • Matthew L. Meyerson MD, PhD
  14. Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA

    • Charles S. Fuchs MD, MPH
  15. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Albert C. Koong MD, PhD

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Disclosure

Dr. Yurgelun has received prior research funding from Myriad Genetic Laboratories, Inc. Dr. Syngal has served as a consultant for Myriad Genetic Laboratories, Inc. Dr. Fuchs has served as a consultant for Lilly, Sanofi, Mayer, Merck, Entrinsic Health, Five Prime,Therapeutics, Agios, Gilead Sciences, Dicerna, Merrimack, Taiho Pharmaceutical, KEW Group, and Genentech/Roche. The remaining authors declare no conflicts of interest.

Corresponding author

Correspondence to Matthew B. Yurgelun MD.

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DOI

https://doi.org/10.1038/s41436-018-0009-5