Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype?

Abstract

Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk, controlled for pigmentation phenotype. We report the occurrence of five common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals-and their relationship to such other risk factors as skin, hair, and eye color; freckling; and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of the individuals with CMM, whereas only 56% of the control individuals carried at least one variant (P<.001), a finding independent of strength of family history of melanoma. Three active alleles (Arg151Cys, Arg160Trp, and Asp294His), previously associated with red hair, doubled CMM risk for each additional allele carried (odds ratio 2.0; 95% confidence interval 1. 6-2.6). No such independent association could be demonstrated with the Val60Leu and Asp84Glu variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. We conclude that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype and that these alleles may also negate the protection normally afforded by darker skin coloring in some members of this white population.

Figure 1

Use of allele-specific oligonucleotides for MC1R genotyping. A total of 100 ng each of PCR-amplified MC1R consensus and variant product were bound both independently (homozygote) and as an equimolar mixture (heterozygote) to nylon membranes and were hybridized with consensus or variant 15-base oligonucleotides, as indicated. Hybridization and washing of the [³²P]-labeled oligonucleotides, in the presence of TMAC, differentiates each of the six MC1R variants examined in this study.

Figure 2

Association of MC1R variants with hair color. The percentage of individuals carrying a variant MC1R genotype at the five positions tested is shown, plotted against hair color. At the left-hand side of the graph are the frequencies of the MC1R consensus genotype, represented by “0,” and the total for any variant genotype, represented as “1,” “2,” or “3” variants, in the 818 samples genotyped, for which hair-color data, which sums to 100% for each hair color, are available (table 2). The absolute percentage of each variant position considered to be independently carried on one or both alleles, represented as “1” or “2,” is also plotted against hair color, which is on the right-hand side of the graph.

Figure 3

Association of MC1R variants with skin color. The percentage of individuals carrying a variant MC1R genotype at the five positions tested is shown, plotted against skin color. At the left-hand side of the graph are the frequencies of the MC1R consensus genotype, represented by “0,” and the total for any variant genotype, represented as “1,” “2,” or “3” variants, in the 637 samples genotyped, for which skin-color data, which sums to 100% for each skin color, are available (table 2). The absolute percentage of each variant position considered to be independently carried on one or both alleles, represented as “1” or “2,” is also plotted against skin color, which is on the right-hand side of the graph.