Melanoma, Cutaneous Malignant, Susceptibility To, 5

A number sign (#) is used with this entry because of evidence that susceptibility to cutaneous malignant melanoma-5 (CMM5) is conferred by variation in the gene encoding melanocortin-1 receptor (MC1R; 155555) on chromosome 16q24.

Description

Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010).

For a discussion of genetic heterogeneity of malignant melanoma, see 155600.

Mapping

Bishop et al. (2009) reported a genomewide association study of melanoma conducted in the GenoMEL consortium based on 317,000 tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional 2 cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genomewide screen identified 5 loci with genotypes or imputed SNPs reaching P less than 5 x 10(-7). Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 x 10(-27) for rs258322), 11q14-q21 encompassing TYR (606933) (P = 2.41 x 10(-14) for rs1393350), and 9p21 adjacent to MTAP (156540) and flanking CDKN2A (600160) (P = 4.03 x 10(-7) for rs7023329) (see 155601). MC1R and TYR are associated with pigmentation, freckling, and cutaneous sun sensitivity, well-recognized melanoma risk factors. Bishop et al. (2009) concluded that despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.

Molecular Genetics

Valverde et al. (1996) reported that certain variants of the MC1R gene are more common in individuals with melanoma than in control subjects and that this association is greater than the association between melanoma and skin type. MC1R variants in the second and seventh transmembrane domains were more common in melanoma cases than controls (chi square = 6.75, 1 d.f.; p = 0.0094) with a relative risk to carriers of variant alleles compared with normal homozygotes of 3.91. The asp84-to-glu (D84E; 155555.0003) variant was only present in melanoma cases.

Palmer et al. (2000) studied the relationship between risk of melanoma and MC1R polymorphisms. They reported the occurrence of 5 common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals, as well as the relationship of these polymorphisms 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 persons with CMM, whereas only 56% of the control individuals carried at least 1 variant (P less than 0.01), a finding independent of strength of family history of melanoma. Three 'active' alleles previously associated with red hair, arg151 to cys (R151C; 155555.0004), arg160 to trp (R160W; 155555.0005), and asp294 to his (D294H; 155555.0001), doubled CMM risk for each additional allele carried. No such independent association could be demonstrated with the val60-to-leu (V60L; 155555.0006) and D84E 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. Palmer et al. (2000) concluded that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype, and that these alleles may have also negated the protection normally afforded by darker skin coloring in some members of this white population.

Mutations in the CDKN2A gene (600160) are melanoma predisposition alleles with high penetrance, although they have low population frequencies. In contrast, variants of MC1R confer much lower melanoma risk but are common in European populations. To test for possible modifier effects on melanoma risk, Box et al. (2001) assessed 15 Australian CDKN2A mutation-carrying melanoma pedigrees for MC1R genotype. 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 = 0.01). The presence of a CDKN2A mutation gave a hazard ratio of 13.35, and a 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 the 3 common alleles, R151C, R160W, and D294H, associated with red hair, fair skin, and skin sensitivity to ultraviolet light.

Van der Velden et al. (2001) found that the MC1R variant R151C modified melanoma risk in Dutch families with melanoma. They concluded that the R151C variant is overrepresented in patients with melanoma from families with the p16-Leiden mutation (600160.0003). They suggested that the R151C variant may be involved in melanoma tumorigenesis in a dual manner, both as a determinant of fair skin and as a component in an independent additional pathway, because the variant contributed to increased melanoma risk even after statistical correction for its effect on skin type.

Landi et al. (2006) showed that MC1R variants are strongly associated with BRAF (164757) mutations in nonchronic sun-induced damage melanomas. In this tumor subtype, the risk for melanoma associated with MC1R is due to an increase in risk of developing melanomas with BRAF mutations. Landi et al. (2006) found that BRAF mutations were more frequent in nonchronic sun-induced damage melanoma cases with germline MC1R variants than in those with 2 wildtype MC1R alleles. When the authors categorized patients into 2 groups, homozygous MC1R wildtype versus all others, they found that BRAF mutations were 6 to 13 times as frequent in those with at least 1 MC1R variant allele compared to those with no MC1R variants. Four more tests for interaction between age and MC1R were not significant. Comparison of nonchronic sun-damaged Italian cases with 171 healthy Italian controls showed that the overall melanoma risk was higher by a factor of 3.3 (95% CI 1.5-6.9) in individuals with any MC1R variant allele compared to individuals with no variant alleles and that the risk increased with the number of variant MC1R alleles.