. 2019 Jan;21(1):213-223.

doi: 10.1038/s41436-018-0009-5. Epub 2018 Jul 2.

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

Matthew B Yurgelun^#^{1

2}, Anu B Chittenden^#³, Vicente Morales-Oyarvide^#³, Douglas A Rubinson^{3

4}, Richard F Dunne⁵, Margaret M Kozak⁶, Zhi Rong Qian^{3

7}, Marisa W Welch³, Lauren K Brais³, Annacarolina Da Silva^{3

7}, Justin L Bui⁶, Chen Yuan^{3

8}, Tingting Li⁷, Wanwan Li⁷, Atsuhiro Masuda⁷, Mancang Gu⁷, Andrea J Bullock⁹, Daniel T Chang⁶, Thomas E Clancy¹⁰, David C Linehan¹¹, Jennifer J Findeis-Hosey¹², Leona A Doyle¹³, Aaron R Thorner^{3

14}, Matthew D Ducar¹⁴, Bruce M Wollison¹⁴, Natalia Khalaf⁴, Kimberly Perez^{3

4}, Sapna Syngal^{3

4}, Andrew J Aguirre⁴, William C Hahn^{3

4

14}, Matthew L Meyerson^{3

4

14

15}, Charles S Fuchs^{3

4

16}, Shuji Ogino^{3

7

8

13}, Jason L Hornick¹³, Aram F Hezel⁵, Albert C Koong^{6

17}, Jonathan A Nowak^#^{7

13}, Brian M Wolpin^#^{3

4}

Affiliations

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 Medicine, Brigham & Women's Hospital, Boston, MA, USA.
⁵ Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
⁶ Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, USA.
⁷ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹ Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Surgery, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA.
¹² Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.
¹³ Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 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.

^# Contributed equally.

PMID: 29961768
PMCID: PMC6666401
DOI: 10.1038/s41436-018-0009-5

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

Matthew B Yurgelun et al. Genet Med. 2019 Jan.

. 2019 Jan;21(1):213-223.

doi: 10.1038/s41436-018-0009-5. Epub 2018 Jul 2.

Authors

Affiliations

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 Medicine, Brigham & Women's Hospital, Boston, MA, USA.
⁵ Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
⁶ Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA, USA.
⁷ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹ Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Surgery, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA.
¹² Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.
¹³ Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 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.

^# Contributed equally.

PMID: 29961768
PMCID: PMC6666401
DOI: 10.1038/s41436-018-0009-5

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.

Keywords: Familial pancreatic cancer; Hereditary breast and ovarian cancer; Lynch syndrome; PARP inhibitors.

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Figures

**Figure 1:**
Pathogenic and likely pathogenic germline variants identified among 289 individuals with resected pancreatic adenocarcinoma. Abbreviation: dsDNA, double-strand DNA.

**Figure 2:**
Kaplan-Meier survival curves by germline status: A. Disease-free survival, and B. Overall survival for PDAC patients with any pathogenic/likely pathogenic germline cancer susceptibility gene variant; C. Disease-free survival, and D. Overall survival for PDAC patients with pathogenic/likely pathogenic double-stranded DNA damage repair gene variants. Abbreviations: dsDDR, double-stranded DNA damage repair gene; HR, adjusted hazard ratio; CI, confidence interval.

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous