Germline DNA damage repair gene mutations in pancreatic cancer patients with personal/family histories of pancreas/breast/ovarian/prostate cancer in a Japanese population

Tatsuo Hata; Masamichi Mizuma; Fuyuhiko Motoi; Masaharu Ishida; Hideo Ohtsuka; Kei Nakagawa; Takanori Morikawa; Toru Furukawa; Michiaki Unno

doi:10.1002/ags3.12482

Germline DNA damage repair gene mutations in pancreatic cancer patients with personal/family histories of pancreas/breast/ovarian/prostate cancer in a Japanese population

Ann Gastroenterol Surg. 2021 Jun 28;5(6):853-864. doi: 10.1002/ags3.12482. eCollection 2021 Nov.

Authors

Tatsuo Hata¹, Masamichi Mizuma¹, Fuyuhiko Motoi², Masaharu Ishida¹, Hideo Ohtsuka¹, Kei Nakagawa¹, Takanori Morikawa¹, Toru Furukawa³, Michiaki Unno¹

Affiliations

¹ Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan.
² Department of Surgery I Yamagata University Graduate School of Medical Science Yamagata Japan.
³ Department of Investigative Pathology Tohoku University Graduate School of Medicine Sendai Japan.

Abstract

Aim: Cancer patients with personal/family histories of pancreatic/breast/ovarian/prostate cancer are associated with a higher likelihood of harboring DNA damage repair (DDR)-related germline mutations. Here, we aimed to obtain a better understanding of DDR-related germline mutations in Japanese pancreatic ductal adenocarcinoma (PDAC) patients with personal and/or family histories of BRCA-related cancers of the pancreas, breast, ovary, and prostate.

Methods: We performed next-generation sequencing (NGS) and evaluated germline mutations in nine DDR-related genes (BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, and PMS2) in PDAC patients with personal and/or family histories.

Results: Of 196 patients with PDAC, 39 (19.9%) fulfilled the criteria for at least one family history of pancreatic/breast/ovarian/prostate cancer in first-degree relatives (sibling-sibling or parent-child) or the personal history of these malignancies. Targeted NGS revealed that four (10.2%) of 39 patients with personal/family histories harbored deleterious germline mutations-two in BRCA2, one in ATM, and one in MLH1. Both the BRCA2 variants showed frameshift mutations due to short insertion/deletions. In the 39 patients undergoing NGS, a similar distribution of the clinicopathological characteristics was observed between those with deleterious mutations/variants of unknown significance (VUSs) and with benign/wild types. Patients with deleterious germline mutations/VUSs in DDR-related genes showed a significantly more favorable prognosis than those with benign mutations/wild-type genes (hazard ratio: 0.160, P = .040).

Conclusions: A significant fraction of PDAC patients with personal/family histories of BRCA-related cancers harbored deleterious germline mutations in DDR-related genes. DDR-related germline gene mutations might be a favorable prognostic factor in patients with pancreatic cancer.

Keywords: familial pancreatic cancer; germline mutation; homologous recombination repair; mismatch repair; next‐generation sequencing.