Polymorphism in the nuclear excision repair gene ERCC2/XPD: association between an exon 6–exon 10 haplotype and susceptibility to cutaneous basal cell carcinoma†

Cutaneous basal cell carcinoma (BCC) risk is mediated by interactions between ultraviolet radiation (UVR) and host factors, including DNA repair efficiency. We investigated the association between BCC risk and SNPs in exon 6 (c.466C>A, dbSNP238406:g.C>A; designated C/A 1 5 6 ), exon 10 (c.932G>A, dbSNP1799793:g.G>A; designated G/A 3 1 2 ), and exon 23 (c.2251A>C, dbSNP13181:g.A>C; designated A/C 7 5 1 ) of the nucleotide excision repair gene, XPD (ERCC2; excision repair cross-complementing repair deficiency, complementation 2 [xeroderma pigmentosum D]). XPD genotype frequencies were not significantly different in 509 cases and 379 controls, although AA 1 5 6 (odds ratio [OR]=0.61, 95% confidence interval [CI]=0.37-1.01, P=0.052) and AA 3 1 2 (OR=0.65, 95% CI=0.40-1.05, P=0.08) were linked with reduced risk. A 1 5 6 -A 3 1 2 and A 1 5 6 -A 3 1 2 -A 7 5 1 haplotype frequencies however, were significantly lower in cases than controls (OR=0.12, 95% CI=0.05-0.31, P<0.001; OR=0.10, 95% CI=0.03-0.33, P<0.001). We confirmed the robustness of these findings by showing significant associations of the haplotypes with risk in two randomly selected equal sized groups of cases and controls and, using the false positive report probability (FPRP) approach (FPRP values <0.001 and<0.004, respectively). A 1 5 6 -A 3 1 2 was similarly associated with reduced risk in subgroups, including cases with no family history of skin cancer, with only BCC on the head/neck, and those with a high rate of increase in BCC numbers. The association was not dependent on gender, age, or extent of UVR exposure. A 1 5 6 -A 3 1 2 was found in 6.3% of controls and the corresponding risk haplotype, C 1 5 6 -G 3 1 2 (OR=1.65, 95% CI=1.21-2.26, P=0.002) in 35.4% of controls. We interpret these data as showing that XPD SNP mediate susceptibility to BCC.