Polymorphisms in the DNA Repair Genes XPC, XPD, and XPG and Risk of Cutaneous Melanoma: a Case-Control Analysis

Sunlight causes DNA damage, including bulky lesions that are removed effectively by the nucleotide-excision repair (NER) pathway. There are at least eight core NER proteins participating in the pathway, and genetic variations in their genes may alter NER functions. We hypothesized that some NER variants are associated with risk of cutaneous melanoma. In a hospital-based case-control study of 602 non-Hispanic White patients with cutaneous melanoma and 603 age- and sex-matched cancer-free controls, we genotyped five common non-synonymous single-nucleotide polymorphisms identified to date and assessed their associations with risk of cutaneous melanoma. We found that a significantly increased risk of cutaneous melanoma was associated with XPD 751Lys/Gln [adjusted odds ratio (OR), 1.55 and 95% confidence interval (95% CI), 1.12-2.16] and XPD 751Gln/Gln (OR, 1.66; 95% CI, 1.03-2.68) genotypes compared with the XPD 751Lys/Lys genotype as well as XPD312Asp/Asn (OR, 1.54; 95% CI, 1.11-2.12) and XPD312Asn/Asn (OR, 1.75; 95% CI, 1.05-2.90) genotypes compared with the XPD 312Asp/Asp genotype. This increased risk was not observed in the other three XPC and XPG single-nucleotide polymorphisms. Moreover, the number of the observed XPD at-risk genotypes (i.e., 312Asn/Asn+Asn/Asp and 751Gln/Gln+Lys/Gln ) was associated with cutaneous melanoma risk in a dose-response manner (OR, 1.47; 95% CI, 0.97-2.23 for one at-risk genotype; OR, 1.83; 95% CI, 1.29-2.61 for two at-risk genotypes; P trend < 0.001). However, we found no evidence of any interaction between XPD genotypes with XPC and XPG genotypes or the known risk factors. We concluded that genetic variants of the XPD gene might serve as biomarkers for susceptibility to cutaneous melanoma. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2526–32)