2025-09-11 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
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東アジアにおける23種類のがんに対するCHEK2機能解析を伴う症例対照研究:リスク推定と臨床的推奨事項 Case-Control Study for 23 Cancer Types With Functional Analysis of CHEK2: Risk Estimation and Clinical Recommendations in East Asia
Yuri Takehara, MD, Yoshiaki Usui, MD, Lenka Stolařová, PhD, Petra Kleiblova, MD, Yusuke Iwasaki, ME, Todd A. Johnson, PhD, Makoto Hirata, MD, … , and Yukihide Momozawa, DVM, PhD
JCO Precision Oncology Published:September 02, 2025
DOI:https://doi.org/10.1200/PO-24-009
Abstract
Purpose
CHEK2 is the frequently detected cancer-predisposing gene in female breast cancer. In addition, the association with the risks of other cancer types has been suggested, and clinical management has also been discussed. Although clinical relevance of germline variants differs across population, there is little evidence of the clinical relevance of CHEK2 germline variants in East Asia.
Methods
Targeted sequencing and functional analyses of missense variants for the coding region of CHEK2 in 111,571 East Asian individuals were performed. Variants classified as pathogenic/likely pathogenic in ClinVar, predicted loss-of-function, or functionally impaired in functional analysis were defined as germline damaging variants (gDVs). We evaluated the association between CHEK2 gDVs and the risk of 23 cancer types. We also compared the clinical characteristics of carriers and noncarriers among patients with CHEK2-associated cancers.
Results
We identified 77 gDVs including 36 functionally impaired missense variants. CHEK2 gDVs were significantly associated exclusively with prostate cancer (odds ratio [OR], 1.8 [95% CI, 1.2 to 2.6]; P = 1.7 × 10-3), in addition to female breast cancer (OR, 1.8 [95% CI, 1.3 to 2.6]; P = 1.2 × 10-3), among 23 cancer types. There were no differences in age at diagnosis, pathologic status, and prognosis between carriers and noncarriers. Besides, there was no association with the risk of cancer types with high incidence rates in East Asian countries.
Conclusion
CHEK2 gDVs were associated with female breast and prostate cancer risks in East Asia. The necessity of additional systematic clinical management for all CHEK2 gDV carriers should be carefully discussed, and standard cancer screening is recommended unless no other clinical features suggestive of cancer predisposition are noted in East Asia.
