Melanocortin-1 receptor gene variants determine the risk of nonmelanoma skin cancer independently of fair skin and red hair

Melanocortin-1 receptor (MC1R) gene variants are associated with fair skin and red hair and, independently of these, with cutaneous malignant melanoma . The association of MC1R gene variants with nonmelanoma skin cancer is lar gely unknown. A total of 838 subjects were included in the present study: 4 53 patients with nonmelanoma skin cancer and 385 subjects with no skin canc er. The coding sequence of the human MC1R gene was tested using single-stra nded conformation polymorphism analysis followed by sequencing of unknown v ariants. Risk of skin cancer dependent on the various MC1R gene variants wa s estimated using the exposure odds ratio. We investigated whether subjects with MC1R variant alleles were at increased risk of developing nonmelanoma skin cancer and, if so, whether this increased risk was mediated by fair s kin and red hair. A total of 27 MC1R gene variants were found. The number o f carriers of one, two, or three MC1R gene variants was 379 (45.2%), 208 (2 4.8%), and 7 (0.9%), respectively. A strong association between MC1R gene v ariants and fair skin and red hair was established, especially the variants Arg151Cys and Arg160Trp (P<.0001). Carriers of two variant alleles were at increased risk for developing cutaneous squamous cell carcinoma (odds rati o 3.77; 95% confidence interval [CI] 2.11-6.78), nodular basal cell carcino ma (odds ratio 2.26; 95% CI 1.45-3.52), and superficial multifocal basal ce ll carcinoma (odds ratio 3.43; 95% CI 1.92-6.15), compared with carriers of two wild-type alleles. Carriers of one variant allele had half the risk. T he highest relative risks of nonmelanoma skin cancer were found in carriers of the Asp84Glu, His260Pro, and Asp294His variant alleles, and the risk wa s only slightly lower for carriers of the Val60Leu, Val92Met, Arg142His, Ar g151Cys, and Arg160Trp variant alleles. When subjects were stratified by sk in type and hair color, analysis showed that these factors did not material ly change the relative risks. These findings indicate that MC1R gene varian ts are important independent risk factors for nonmelanoma skin cancer.