Germline DNA damage repair gene mutations in pancreatic cancer patients with personal/family histories of pancreas/breast/ovarian/prostate cancer in a Japanese population.
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.
['Hata|Tatsuo|T|https://orcid.org/0000-0001-5155-2508', 'Mizuma|Masamichi|M|https://orcid.org/0000-0002-6436-5477', 'Motoi|Fuyuhiko|F|https://orcid.org/0000-0001-7601-8395', 'Ishida|Masaharu|M|https://orcid.org/0000-0003-2113-4043', 'Ohtsuka|Hideo|H|https://orcid.org/0000-0001-5503-2163', 'Nakagawa|Kei|K|https://orcid.org/0000-0002-3058-5674', 'Morikawa|Takanori|T|https://orcid.org/0000-0003-2014-651X', 'Furukawa|Toru|T|', 'Unno|Michiaki|M|']
germline mutation familial pancreatic cancer homologous recombination repair mismatch repair next‐generation sequencing