MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations

Mutations in the exons of the cyclin-dependent kinase inhibitor gene CDKN2A are melanoma-predisposition alleles which have high penetrance, although t hey have low population frequencies. In contrast, variants of the melanocor tin-1 receptor gene, MC1R, confer much lower melanoma risk but are common i n European populations. Fifteen Australian CDKN2A mutation-carrying melanom a pedigrees were assessed for MC1R genotype, to test for possible modifier effects on melanoma risk. A CDKN2A mutation in the presence of a homozygous consensus MC1R genotype had a raw penetrance of 50%, with a mean age at on set of 58.1 years. When an MC1R variant allele was also present, the raw pe netrance of the CDKN2A mutation increased to 84%, with a mean age at onset of 37.8 years (P=0.1). The presence of a CDKN2A mutation gave a hazard rati o of 13.35, and the hazard ratio of 3.72 for MC1R variant alleles was also significant. The impact of MC1R variants on risk of melanoma was mediated l argely through the action of three common alleles, Arg151Cys, Arg160Trp, an d Asp294His, that have previously been associated with red hair, fair skin, and skin sensitivity to ultraviolet light.