RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability
Open accessAbstract
The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.
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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 [18]
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- Authors
- Heikkinen, K.
- Affiliations
- Oulu University Hospital (FI)
- Corresponding author
- Heikkinen, K.
- Venue
- Carcinogenesis
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-12-12
- Volume
- 27
- Issue
- 8
- Pages
- 1593-1599
- ISSN
- 0143-3334 (ISSN-L)
- 1460-2180
- PMC
- PMC3006189
- OpenAlex
- W2137466745
- Cited by
- 208
- References
- 31
- Citations by year
- 2025: 7 · 2024: 6 · 2023: 12 · 2022: 8 · 2021: 10 · 2020: 11 · 2019: 5 · 2018: 10 · 2017: 12 · 2016: 10 · 2015: 11 · 2014: 12 · 2013: 18 · 2012: 8
- FWCI
- 5.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Carcinogenesis (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Funders
- National Cancer Institute (R13CA162528, P30CA008748)
- National Institute of General Medical Sciences (R01GM056888)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- RAD50, NBS1, Mre11 complex, hereditary breast cancer, cancer susceptibility genes, genomic instability, founder mutation, haploinsufficiency, BRCT domain, chromosomal rearrangements, Finnish population
- MeSH terms
- Adult, Aged, Aged, 80 and over, Breast Neoplasms, DNA-Binding Proteins, Female, Genotype, Haplotypes, Humans, Male, Mass Screening, Middle Aged, Mutation, Nuclear Proteins, Pedigree, T-Lymphocytes, Gene Rearrangement, Cohort Studies, Case-Control Studies, Acid Anhydride Hydrolases, Cell Cycle Proteins, Microsatellite Repeats, Genetic Predisposition to Disease, Cytogenetic Analysis, Genomic Instability, DNA Repair Enzymes
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