The XRCC1 Arg399Gln polymorphism, sunburn, and non-melanoma skin cancer: evidence of gene-environment interaction.

XRCC1, a protein directly involved in the repair of DNA base damage, contains at least three common polymorphisms. One of these, the codon 399 arg-->gln variant, has been associated with several cancer-related biomarkers, suggesting it may have functional significance in exposure-induced cancers. However, results from case-control studies have yielded conflicting results. We investigated the XRCC1 arg399gln polymorphism and its interaction with carcinogen exposure in a large, population-based case-control study of non-melanoma skin cancer. Cases were derived from an incident survey of all newly diagnosed non-melanoma skin cancer in New Hampshire, and controls were population based and frequency matched to cases on age and sex (n = 1176). Exposure information was derived from a detailed interviewer-administered questionnaire, and XRCC1 genotype was determined from blood-derived DNA using a PCR-RFLP method. Overall, the XRCC1 homozygous variant gln399gln genotype was related to a significantly reduced risk of both basal cell [BCC; odds ratio (OR) 0.7, 95% confidence interval 0.4-1.0] and squamous cell carcinoma (SCC; OR 0.6, 95% confidence interval 0.3-0.9). There was no significant gene-environment interaction of the variant XRCC1 genotype and a history of therapeutic X-ray exposure. However, there was a statistically significant multiplicative interaction of XRCC1 genotype and lifetime number of sunburns in SCC [likelihood ratio test (2 d.f.), P < 0.02]. Although the absolute risk of SCC associated with sunburns was similar across genotypes, the relative risk of SCC associated with painful sunburn history was significantly higher for homozygous variants than wild types (OR 6.8 for gln399gln and 1.5 for arg399arg). In summary, our data show that the homozygous XRCC1 variant (gln399gln) is associated with a lower risk of non-melanoma skin cancer and suggest that the etiology of sunburn-related SCC may be significantly different by XRCC1 genotype. These data, using the classic skin carcinogenesis model, provide new insight on the role of the XRCC1 399 polymorphism in neoplasia and may help explain the conflicting results relating this polymorphism to cancer risk at various sites.