A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer.
An acquired genetic instability, resulting from the loss of some types of DNA repair, is an early event in the development of a subset of human cancers. The involvement of BRCA1 and BRCA2 in the homologous recombination repair (HRR) of double-strand breaks in DNA implicates this pathway in the suppression of breast cancer. A family of proteins related to human RAD51, including XRCC2, are essential components of this repair pathway. Using site-directed mutagenesis of XRCC2, we show that non-conservative substitution or deletion of amino acid 188 of XRCC2 can significantly affect cellular sensitivity to DNA damage, and that a polymorphic variant at this site (R188H ), present on 6% of chromosomes in the population, has a weak effect on damage sensitivity. We tested the hypothesis that the R188H polymorphism could be a low-penetrance susceptibility factor for breast cancer, by genotyping 521 women with breast cancer and a total of 895 control women. Carriage of the rare allele of XRCC2 R188H was associated with breast cancer overall [odds ratio 1.3; 95% confidence interval (CI)=(1.0, 1.8)] and when younger-onset cases with a positive family history were compared with older controls with no family history [odds ratio 1.9; 95% CI=(1.0, 3.8)]. These results support the hypothesis that subtle variation in DNA repair capacity may influence cancer susceptibility in the population.
Rafii
Saeed
S
Institute for Cancer Studies, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, S10 2RX, UK.
O'Regan
Paul
P
Xinarianos
George
G
Azmy
Iman
I
Stephenson
Tim
T
Reed
Malcolm
M
Meuth
Mark
M
Thacker
John
J
Cox
Angela
A
D000368:Aged; D019943:Amino Acid Substitution; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D002470:Cell Survival; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D016685:Mitomycin; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011110:Polymorphism, Genetic
D004268:DNA-Binding Proteins; C113187:XRCC2 protein, human; D016685:Mitomycin