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.

1st Faculty of Medicine Institute of Biology and Medical Genetics Charles University and General University Hospital Prague Prague Czech Republic

1st Faculty of Medicine Institute of Medical Biochemistry and Laboratory Diagnostics Charles University and General University Hospital Prague Prague Czech Republic

Cancer Cell Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Genetic Medicine and Services National Cancer Center Hospital Tokyo Japan

Department of Genetic Medicine Kyoundo Hospital Sasaki Foundation Tokyo Japan

Department of Human Genetics Yokohama City University Graduate School of Medicine Yokohama Japan

Department of Molecular Biology Institute for Advanced Medical Sciences Nippon Medical School Tokyo Japan

Division of Genetics and Population Health QIMR Berghofer Medical Research Institute Brisbane QLD Australia

Division of Genome Biology National Cancer Center Research Institute Tokyo Japan

Division of Molecular Pathology Department of Cancer Biology Institute of Medical Science The University of Tokyo Tokyo Japan

Institute of Pathophysiology 1st Faculty of Medicine Charles University Prague Czech Republic

Laboratory for Cancer Genomics RIKEN Center for Integrative Medical Sciences Yokohama Japan

Laboratory for Genotyping Development RIKEN Center for Integrative Medical Sciences Yokohama Japan

Laboratory of Clinical Genome Sequencing Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan

Laboratory of Complex Trait Genomics Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan

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