Human Molecular Genetics, 2002, Vol. 11, No. 12 1433-1438
© 2002 Oxford University Press
A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer
1Institute for Cancer Studies, Division of Genomic Medicine and 2Section of Surgical and Anaesthetic Sciences, Division of Clinical Sciences, University of Sheffield Medical School, Sheffield, S10 2RX, UK, 3Medical Research Council, Radiation and Genome Stability Unit, Harwell, OX11 0RD, UK, and 4Department of Histopathology, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK
Received February 6, 2002; Accepted March 27, 2002
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.
* To whom correspondence should be addressed at: Institute for Cancer Studies, Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK. Tel:+44 (0)114 271 2373; Fax:+44 (0)114 271 3515; Email: a.cox{at}sheffield.ac.uk
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