TY - JOUR
T1 - Germline DNA damage repair gene mutations in pancreatic cancer patients with personal/family histories of pancreas/breast/ovarian/prostate cancer in a Japanese population
AU - Hata, Tatsuo
AU - Mizuma, Masamichi
AU - Motoi, Fuyuhiko
AU - Ishida, Masaharu
AU - Ohtsuka, Hideo
AU - Nakagawa, Kei
AU - Morikawa, Takanori
AU - Furukawa, Toru
AU - Unno, Michiaki
N1 - Funding Information:
Funding: This work was supported by grants from the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC, to TH), the Uehara Memorial Foundation (to TH).
Publisher Copyright:
© 2021 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterology.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
KW - familial pancreatic cancer
KW - germline mutation
KW - homologous recombination repair
KW - mismatch repair
KW - next-generation sequencing
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U2 - 10.1002/ags3.12482
DO - 10.1002/ags3.12482
M3 - Article
AN - SCOPUS:85118392013
SN - 2475-0328
VL - 5
SP - 853
EP - 864
JO - Annals of Gastroenterological Surgery
JF - Annals of Gastroenterological Surgery
IS - 6
ER -
