Association of Germline Variants in Human DNA Damage Repair Genes and Response to Adjuvant Chemotherapy in Resected Pancreatic Ductal Adenocarcinoma

Haijie Hu; Yayun Zhu; Ning Pu; Richard A Burkhart; William Burns; Daniel Laheru; Lei Zheng; Jin He; Michael G Goggins; Jun Yu

doi:10.1016/j.jamcollsurg.2020.06.019

Association of Germline Variants in Human DNA Damage Repair Genes and Response to Adjuvant Chemotherapy in Resected Pancreatic Ductal Adenocarcinoma

J Am Coll Surg. 2020 Nov;231(5):527-535.e14. doi: 10.1016/j.jamcollsurg.2020.06.019. Epub 2020 Jul 11.

Authors

Haijie Hu¹, Yayun Zhu², Ning Pu³, Richard A Burkhart⁴, William Burns⁴, Daniel Laheru⁵, Lei Zheng⁶, Jin He⁴, Michael G Goggins⁷, Jun Yu⁸

Affiliations

¹ Department of Biliary Surgery, West China Hospital of Sichuan University, Sichuan, China; Department of Surgery, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD.
² Department of Surgery, Baltimore, MD; Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
³ Department of Surgery, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD.
⁴ Department of Surgery, Baltimore, MD; Department Oncology, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.
⁵ Department Pathology, Baltimore, MD; Department Oncology, Baltimore, MD; Department Medicine, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; The Skip Viragh Center for Pancreas Cancer, Baltimore, MD; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD.
⁶ Department of Surgery, Baltimore, MD; Department Oncology, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; The Skip Viragh Center for Pancreas Cancer, Baltimore, MD; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD.
⁷ Department Pathology, Baltimore, MD; Department Medicine, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; The Skip Viragh Center for Pancreas Cancer, Baltimore, MD.
⁸ Department of Surgery, Baltimore, MD; The Johns Hopkins University School of Medicine The Pancreatic Cancer Precision Medicine Center of Excellence, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD. Electronic address: jyu41@jhmi.edu.

PMID: 32659497
DOI: 10.1016/j.jamcollsurg.2020.06.019

Abstract

Background: The frequency and significance of the germline variants in DNA damage repair genes still need to be elucidated in patients with sporadic pancreatic ductal adenocarcinoma (PDAC). Our purpose was to determine whether germline variants in DNA damage repair genes were associated with survival of patients with sporadic PDAC.

Study design: We retrospectively identified 854 patients with sporadic PDAC with germline DNA sequenced in targeted 22 DNA damage repair genes by next-generation sequencing. Outcomes were compared in terms of clinicopathologic features, disease-free survival (DFS), and overall survival (OS).

Results: Nineteen patients had deleterious mutations; 103 had variant(s) of unknown significance (VUS). Germline DNA damage repair deleterious variant carriers had superior DFS (median, 19.1 months vs 11.9 months, p = 0.012) and OS (median, 29.7 months vs 20.2 months, p = 0.034), as compared with wild-type patients. Germline DNA damage repair VUS variant carriers also had superior DFS when compared with wild-type patients. In subgroup analysis, this improved survival was limited to patients receiving adjuvant chemotherapy, deleterious variant carriers vs wild-type patients DFS (median 36.3 months vs 13.1 months, p = 0.006) and OS (median 43.7 months vs 24.3 months, p = 0.045), VUS variant carriers vs wild-type patients DFS (16.5 months vs 13.1 months, p = 0.007).

Conclusions: Having a deleterious variant in a DNA damage repair gene is associated with improved survival after resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy
Adenocarcinoma / genetics*
Adenocarcinoma / mortality
Adenocarcinoma / surgery
Aged
Carcinoma, Pancreatic Ductal / drug therapy
Carcinoma, Pancreatic Ductal / genetics*
Carcinoma, Pancreatic Ductal / mortality
Carcinoma, Pancreatic Ductal / surgery
Chemotherapy, Adjuvant
DNA Damage*
Female
Germ-Line Mutation*
Humans
Male
Middle Aged
Pancreatectomy
Pancreatic Neoplasms / drug therapy
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / mortality
Pancreatic Neoplasms / surgery
Retrospective Studies
Survival Rate