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 Otsuka, Kei Nakagawa, Takanori Morikawa, Toru Furukawa, Michiaki Unno

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)853-864
Number of pages12
JournalAnnals of Gastroenterological Surgery
Volume5
Issue number6
DOIs
Publication statusPublished - 2021 Nov

Keywords

  • familial pancreatic cancer
  • germline mutation
  • homologous recombination repair
  • mismatch repair
  • next-generation sequencing

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

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