2025-11-26 理化学研究所,東京大学医科学研究所,日本医科大学,国立がん研究センター,佐々木研究所附属杏雲堂病院,愛知県がんセンター
がんごとの四つのDNAミスマッチ修復遺伝子の病的バリアント保持率
<関連情報>
- https://www.riken.jp/press/2025/20251126_1/index.html
- https://www.nature.com/articles/s43856-025-01231-9
バイオバンクジャパンにおけるリンチ症候群関連変異体の全癌罹患率、リスク、臨床的および人口統計学的特徴 Pan-cancer prevalence, risk, and clinical and demographic characteristics of Lynch Syndrome-associated variants in BioBank Japan
Keijiro Mizukami,Yoshiaki Usui,Yusuke Iwasaki,Kouya Shiraishi,Makoto Hirata,Yoichiro Kamatani,Mikiko Endo,Satoshi Takahashi,Yoshiki Mochizuki,Mitusyo Yamaguchi,Takashi Kohno,Koichi Matsuda,Kokichi Sugano,Teruhiko Yoshida,Hidewaki Nakagawa,Chikashi Terao,Yuriko N. Koyanagi,Keitaro Matsuo,Yoshinori Murakami,Amanda B. Spurdle & Yukihide Momozawa
Communications Medicine Published:13 November 2025
DOI:https://doi.org/10.1038/s43856-025-01231-9 An unedited version
Abstract
Background
Although germline testing for DNA mismatch repair (MMR) genes is routinely performed, clinical guidelines highlight evidence gaps due to limited populations and biases. We examined germline pathogenic variants of MMR genes (MLH1, MSH2, MSH6, and PMS2) in 112,927 unselected individuals from BioBank Japan.
Methods
We analyzed 74,085 cancer patients with 23 cancer types and 38,842 controls matched by sex, age, and hospital area from BioBank Japan, collected between April 2003 and March 2018. Germline pathogenic variants in the coding regions and 2 bp flanking intronic sequences of MMR genes were identified using a multiplex PCR-based target sequencing method. We examined associations with cancer types and demographic characterization of the pathogenic variants, comparing findings to existing clinical guidelines.
Results
Here we show 228 pathogenic variants identified in MMR genes, with pathogenic MSH6 variants most frequently observed in endometrial cancer and 12 other significant associations. Twelve other significant associations are noted across a broad range of odds ratios, whereas pancreatic cancer exhibits no such association. Pathogenic variant carriers are diagnosed up to 12.4 years earlier than non-carriers, and colorectal and gastric cancers are diagnosed up to 16.4 years later than indicated by the guidelines. Higher carrier frequencies are observed in patients with both colorectal and endometrial cancers (24.8%) and in those with endometrial cancer and a family history of endometrial (26.0%) or colorectal (16.1%) cancers.
Conclusions
This study provides critical insights for clinical guidelines on the associations between cancer types, age at diagnosis, and carrier frequency.
Plain Language Summary
Lynch syndrome is an inherited condition that raises the risk of cancers such as colorectal and endometrial cancer. Most past studies on this condition focused on small or selected groups, which may not represent the general population. In this study, we examined genetic and clinical data regarding Lynch syndrome from a large, unselected group of people in Japan. We found how often people carried inherited changes linked to Lynch syndrome and how these changes related to cancer type and age at diagnosis. Our results also revealed differences in amount of people who have inherited changes linked to Lynch syndrome depending on whether people had multiple cancers or a family history of cancer. These insights may help improve recommendations for genetic testing and cancer screening.
