Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations
Abstract
Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.
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CHEK2, ATM, NBS1, RAD50, TOPBP1, and RAD51C are mutated in breast cancer patients.
“Correspondingly, these and other genes functioning in the DNA damage response, such as CHEK2, ATM, NBS1, RAD50, TOPBP1 and RAD51C, are mutated in breast cancer patients [12–21].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [12]
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- Authors
- The CHEK2-Breast Cancer Consortium
- Venue
- Nature Genetics
- Published
- 2002-04-22
- Volume
- 31
- Issue
- 1
- Pages
- 55-59
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2010378709
- Cited by
- 1,104
- References
- 19
- Citations by year
- 2026: 7 · 2025: 32 · 2024: 22 · 2023: 36 · 2022: 26 · 2021: 37 · 2020: 43 · 2019: 26 · 2018: 32 · 2017: 45 · 2016: 48 · 2015: 43 · 2014: 44 · 2013: 40 · 2012: 45
- FWCI
- 38.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Cancer Research Institute
- Cancer Research UK
- KWF Kankerbestrijding
- Deutsche Krebshilfe
- National Cancer Institute
- Abramson Family Cancer Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- CHEK2, breast cancer susceptibility, BRCA1, BRCA2, male breast cancer, truncating mutations, DNA repair, cancer risk assessment
- MeSH terms
- Breast Neoplasms, Female, Genetic Testing, Heterozygote, Humans, Male, Mutation, Pedigree, Protein Kinases, Risk Factors, Case-Control Studies, Protein Serine-Threonine Kinases, Sequence Deletion, Microsatellite Repeats, Genes, BRCA1, Genes, BRCA2, Checkpoint Kinase 2
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