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Common Single-Nucleotide Polymorphisms in DNA Double-Strand Break Repair Genes and Breast Cancer Risk

¹ Cancer Research UK Genetic Epidemiology Unit and ² Cancer Research UK Department of Oncology, Strangeways Research Laboratory; ³ Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and ⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institutes, NIH, Rockville, Maryland

Requests for reprints: Karen A. Pooley, Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom. Phone: 44-1223-741618; Fax: 44-1223-740147. E-mail: karenp{at}srl.cam.ac.uk

The proteins involved in homologous recombination are instrumental in the error-free repair of dsDNA breakages, and common germ-line variations in these genes are, therefore, potential candidates for involvement in breast cancer development and progression. We carried out a search for common, low-penetrance susceptibility alleles by tagging the common variation in 13 genes in this pathway in a two-stage case-control study. We genotyped 100 single-nucleotide polymorphisms (SNP), tagging the 655 common SNPs in these genes, in up to 4,470 cases and 4,560 controls from the SEARCH study. None of these tagging SNPs was associated with breast cancer risk, with the exception of XRCC2 rs3218536, R188H, which showed some evidence of a protective association for the rare allele [per allele odds ratio, 0.89; 95% confidence intervals (95% CI), 0.80-0.99; P trend = 0.03]. Further analyses showed that this effect was confined to a risk of progesterone receptor positive tumors (per rare allele odds ratio, 0.78; 95% CI, 0.66-0.91; P trend = 0.002). Several other SNPs also showed receptor status-specific susceptibility and evidence of roles in long-term survival, with the rare allele of BRIP1 rs2191249 showing evidence of association with a poorer prognosis (hazard ratio per minor allele, 1.20; 95% CI, 1.07-1.36; P trend = 0.002). In summary, there was little evidence of breast cancer susceptibility with any of the SNPs studied, but larger studies would be needed to confirm subgroup effects. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3482–9)