MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations

Abstract

Mutations in the exons of the cyclin-dependent kinase inhibitor gene CDKN2A are melanoma-predisposition alleles which have high penetrance, although they have low population frequencies. In contrast, variants of the melanocortin-1 receptor gene, MC1R, confer much lower melanoma risk but are common in European populations. Fifteen Australian CDKN2A mutation-carrying melanoma 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 onset of 58.1 years. When an MC1R variant allele was also present, the raw penetrance of the CDKN2A mutation increased to 84%, with a mean age at onset of 37.8 years (P=.01). The presence of a CDKN2A mutation gave a hazard ratio 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 largely through the action of three common alleles, Arg151Cys, Arg160Trp, and Asp294His, that have previously been associated with red hair, fair skin, and skin sensitivity to ultraviolet light.

Figure 1

Expected survival curves (Cox proportional-hazards model) for melanoma versus CDKN2A and MC1R genotypes. For clarity, the lines joining the points of the empirical survivor functions (black diamonds [⧫] denote CDKN2A mutation + MC1R variant; white diamonds [◊] denote CDKN2A mutation + MC1R wt; white triangles [▿] denote CDKN2A wt + MC1R variant) have been omitted.