We performed genetic association studies in a population-based breast cancer case–control study analysing polymorphisms in genes involved in homologous recombination ( NBS1 , RAD52 , RAD51 , XRCC2 and XRCC3 ) and non-homologous end-joining ( KU70 / 80 and LIG4 ). These DNA double-strand break repair genes are candidates for breast cancer susceptibility. Genotype results were available for up to 2205 cases and 1826 controls. In the homologous recombination (HR) pathway, genotype frequencies differed between cases and controls for two polymorphisms in XRCC3 ; T241M ( P =0.015) and IVS5 A>G at nt 17893 ( P =0.008). Homozygous carriers of M241 were associated with an increased risk [odds ratio (OR) MM versus TT=1.3 (95% confidence interval (CI) 1.1–1.6)], while the rare allele of IVS5A>G was associated with a dominant protective effect [OR AG versus AA=0.8 (0.7–0.9)]. The association of a rare variant in XRCC2 (R188H) was marginally significant [ P =0.07; OR HH versus RR=2.6 (1.0–6.7)]. In the non-homologous end-joining (NHEJ) pathway, a polymorphism in LIG4 (T>C at nt 1977) was associated with a decrease in breast cancer risk [ P =0.09; OR CC versus TT=0.7 (0.4–1.0)]. No significant association was found for 12 other polymorphisms in the other genes studied. For XRCC3 , we found evidence for four common haplotypes and four rarer ones that appear to have arisen by recombination. Two haplotypes, AGC and GGC, were associated with non-significant reductions in breast cancer risk, and the rare GAT haplotype was associated with a significantly increased risk. These data provide some evidence that variants in XRCC2 and LIG4 alter breast cancer risk, together with stronger evidence that variants of XRCC3 are associated with risk. If these results can be confirmed, understanding the functional basis should improve our understanding of the role of DNA repair in breast carcinogenesis.

Endogenous hormone exposure is known to alter breast cancer susceptibility and genes responsive to such hormones are plausible candidates for predisposition genes. We have examined polymorphisms in genes for two members of the nuclear receptor superfamily which are expressed in breast tissue and known to moderate rates of cell proliferation in a case–control association study: the androgen receptor (AR) and the vitamin D receptor (VDR). We have used two series of Caucasian female breast cancer cases, one incident and one prevalent, and compared both with two sets of matched controls from the East Anglian region of Britain. Since the results are similar in the two series we have combined them. The AR poly[Gly]_n and poly[Gln]_n tracts were genotyped in a total of 508 female breast cancer cases and 426 controls. The VDR TaqI polymorphism was analysed in 951 cases and 627 controls drawn from the same population series. There were no significant differences between cases and controls for either the AR or VDR polymorphisms. Compared with individuals with two short alleles (<22 repeats) of the AR poly[Gln]_n tract, the odds ratios and 95% confidence intervals (95% CI) for individuals with one or two long alleles were 0.82 (95% CI 0.62–1.09) and 1.31 (95% CI 0.87–1.97), respectively. Heterozygotes and homozygotes for the VDR TaqI cutting site had odds ratios of 1.01 (95% CI 0.81–1.27) and 0.97 (95% CI 0.71–1.32), respectively. None of the AR or VDR polymorphisms investigated has a major effect on risk of breast cancer in the British population.