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

Abstract

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)

Genetic variants at the miR-124 binding site on the cytoskeleton-organizing IQGAP1 gene confer differential predisposition to breast cancer

“…A few other studies have also shown an association between genetic variations and PR status. In a case-control study with more than 9,000 subjects, Pooley et al (35) found that a coding SNP (rs3218536) in one of the DNA double-strand break repair genes, XRCC2, was strongly associated with risk of developing PR-positive breast cancer. In another study, Synowiec et al (36) reported an association between the RAD51-135G/C polymorphism and PR expression (OR=6.33; 95% CI=1.15-35.01).…”

Genetic variation in genes interacting with BRCA1/2 and risk of breast cancer in the Cypriot population

“…Our group as part of an ongoing investigation has studied genetic variation in DNA repair genes in relation to breast cancer risk in the Cypriot population and has reported a number of SNPs that modify breast cancer risk [35,41]. A number of large studies which focused on the contribution of common SNPs in DNA repair genes in breast cancer, using tagging SNP approaches have also been completed [9,42,43]. In this case-control study, we evaluated both functional as well as tagging SNPs in DNA repair genes in relation to breast cancer risk in Cypriot women.…”

Telomere Length in Prospective and Retrospective Cancer Case-Control Studies

“…The SEARCH Breast study (42) is an ongoing populationbased study, recruiting cases ascertained through the Eastern Cancer Registration and Information Centre (http://www.ecric. org.uk/), a population-based cancer registry covering the counties of Cambridgeshire, Norfolk, Suffolk, Bedfordshire, Hertfordshire, and Essex.…”