Population-Based Study of Natural Variation in the Melanocortin-1 Receptor Gene and Melanoma

Abstract

Natural variation in the coding region of the melanocortin-1 receptor (MC1R) gene is associated with constitutive pigmentation phenotypes and development of melanoma and nonmelanoma skin cancers. We investigated the effect of MC1R variants on melanoma using a large, international populationbased study design with complete determination of all MC1R coding region variants. Direct sequencing was completed for 2,202 subjects with a single primary melanoma (controls) and 1,099 subjects with second or higher-order primary melanomas (cases) from Australia, the United States, Canada, and Italy. We observed 85 different MC1R variants, 10 of which occurred at a frequency >1%. Compared with controls, cases were more likely to carry two previously identified red hair (''R'') variants [D84E, R151C, R160W, and D294H; odds ratio (OR), 1.6; 95% confidence interval (95% CI), 1.1-2.2]. This effect was similar among individuals carrying one R variant and one r variant (defined as any non-R MC1R variant; OR, 1.6; 95% CI, 1.3-2.2) and among those carrying only one R variant (OR, 1.5; 95% CI, 1.1-1.9). There was no statistically significant association among those carrying only one or two r variants. Effects were similar across geographic regions and categories of pigmentation characteristics or number of moles. Our results confirm that MC1R is a low-penetrance susceptibility locus for melanoma, show that pigmentation characteristics may not modify the relationship of MC1R variants and melanoma risk, and suggest that associations may be smaller than previously reported in part due to the study design. (Cancer Res 2006; 66(18): 9330-7)

Melanoma Epidemiology and Prevention

“…It is one of the major genes that determine skin and hair colors, although there is evidence that it acts via pigmentary and non-pigmentary pathways to influence melanoma development [56, 120,201]. There are many common variants of MC1R [121], but only six of them are usually referred to as "red hair color phenotype" or "R" variants (associated with red hair, fair skin, freckling, poor sun sensitivity) and are associated with a greater-than-twofold increased risk of melanoma [56,201,243,244]. The other MC1R variants (usually referred to as "r" or "non-RHC") generally have a relatively weak association with red hair color phenotype and have a weaker association with melanoma risk [56,201,243,244].…”

Association of the SLC45A2 gene with physiological human hair colour variation

“…Some allelic variants of the MC1R gene are significantly associated with the overproduction of pheomelanin and therefore red hair and fair skin colour (Rees 2003). Most studies are in agreement that MC1R is involved in malignant melanoma and basal cell carcinoma (e.g., Pastorino et al 2004;Kanetsky et al 2006;Brudnik et al 2008). It is postulated that a product of the ASIP gene may antagonize MC1R receptor activation (Voisey and Van Daal 2002).…”

Familial Melanoma in Italy: A Review

“…No association was observed between the presence of MC1R variants and age at diagnosis. Compared to the SPM patients, MPM cases had a 2-fold increased likelihood of being MC1R variant carriers and a higher probability of carrying two or more variants, as reported by Kanetsky et al (2006) in their large multicenter population-based study. Finally, the analysis showed no specific association between the variant type and the number of CMs (one, two or more).…”