A Prospective Study of XRCC1 Haplotypes and Their Interaction with Plasma Carotenoids on Breast Cancer Risk

The XRCC1 protein is involved in the base excision repair pathway through interactions with other proteins. Polymorphisms in the XRCC1 gene may lead to variation in repair proficiency and confer inherited predisposition to cancer. We prospectively assessed the associations between polymorphisms and haplotypes in XRCC1 and breast cancer risk in a nested case-control study within the Nurses' Health Study (incident cases, n = 1004; controls, n = 1385). We further investigated gene-environment interactions between the XRCC1 variations and plasma carotenoids on breast cancer risk. We genotyped four haplotype-tagging single nucleotide polymorphisms (Arg¹⁹⁴Trp, C26602T, Arg ³⁹⁹Gln, and Gln⁶³²Gln) in the XRCC1 gene. Five common haplotypes accounted for 99% of the chromosomes in the present study population of mostly Caucasian women. We observed a marginally significant reduction in the risk of breast cancer among ¹⁹⁴Trp carriers. As compared with nocarriers, women with at least one ¹⁹⁴Trp allele had a multivariate odds ratio of 0.79 (95% of the confidence interval, 0.60-1.04). The inferred haplotype harboring the ¹⁹⁴Trp allele was more common in controls than in cases (6.6 versus 5.3%, P = 0.07). We observed that the Arg ¹⁹⁴Trp modified the inverse associations of plasma α-carotene level (P, ordinal test for interaction = 0.02) and plasma β-carotene level (P, ordinal test for interaction = 0.003) with breast cancer risk. No suggestion of an interaction was observed between the Arg ¹⁹⁴Trp and cigarette smoking. Our results suggest an inverse association between XRCC1 ¹⁹⁴Trp allele and breast cancer risk. The findings of the effect modification of the Arg ¹⁹⁴Trp on the relations of plasma α- and β-carotene levels with breast cancer risk suggest a potential protective effect of carotenoids in breast carcinogenesis by preventing oxidative DNA damage.