Most cited article - PubMed ID 37449874
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk
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.
- MeSH
- Checkpoint Kinase 2 * genetics MeSH
- Adult MeSH
- Genetic Predisposition to Disease MeSH
- Risk Assessment MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasms * genetics epidemiology MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Germ-Line Mutation MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Asia, Eastern epidemiology MeSH
- Names of Substances
- Checkpoint Kinase 2 * MeSH
- CHEK2 protein, human MeSH Browser
Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37). The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors. Based on these observations, we classified this variant as likely pathogenic.
- Keywords
- Breast cancer, Deep intronic CHEK2 variant, Genetic testing, NGS, RNA analysis,
- MeSH
- Checkpoint Kinase 2 * genetics MeSH
- Adult MeSH
- Genetic Predisposition to Disease * genetics MeSH
- Introns * genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Breast Neoplasms * genetics MeSH
- Ovarian Neoplasms genetics MeSH
- RNA Precursors genetics MeSH
- RNA Splicing * genetics MeSH
- Germ-Line Mutation * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
- Germany MeSH
- Names of Substances
- CHEK2 protein, human MeSH Browser