The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma

Abstract

Melanocyte stimulating hormone (MSH) plays an important role in determining the cutaneous response to ultraviolet radiation and may also influence melanoma progression. We have previously shown that variants of the melanocortin receptor present on melanocytes, MC1R, are associated with sun sensitivity and red hair in a UK population and therefore now consider the gene as a candidate for melanoma susceptibility. We have compared the frequency of known MC1R variants in the second and seventh transmembrane domains in 43 melanoma cases and 44 controls. MC1R variants were more common in cases than controls (chi 2 = 6.75, 1 d.f.; P = 0.0094) with a relative risk to carriers of variant alleles compared with normal homozygotes of 3.91 (95% c.l.: 1.48-10.35), and a population risk attributable to carriers of 34.6% (95% c.i. 10.7-52.1%). The Asp84Glu variant was only present in melanoma cases and appears to be of particular significance. The contribution of variant MC1R alleles was largely independent of skin type. Variants of the MC1R gene are likely to be causally associated with the development of melanoma.

Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries

“…32 It has been proposed that part of the association between melanoma and MC1R variants remains after stratification on phenotypic features suggesting that the effect of MC1R is not exerted entirely through hair and skin color. [7][8][32][33][34][35][36] In the current study, it was not possible to fully evaluate risk in subjects with red hair color or light eye color although the distribution of 2 MC1R variants in these high-risk phenotypic categories was consistent with an increased melanoma risk. Interestingly, there was also a significant association for 2 MC1R variants and melanoma risk in the phenotypically low risk groups (not having red hair color, none/few freckles or none/few nevi).…”

Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria

“…Recent review articles on molecular signalling pathways in melanoma development no longer indicate that the aMSH/melanocortin-1 receptor (MC1R) intracellular signalling pathway has melanoma-inducing or promoting activities. 35,36 In contrast, low activity MC1R variants are associated with increased risk of sporadic melanoma [37][38][39][40] which indicates that decreased and not increased MC1R signalling is associated with melanoma development. Moreover, melanocyte stem cells and therefore most likely also melanoma stem cells, the latter being crucial for melanoma promotion, do not express MC1R and therefore do not react to aMSH analogues.…”

Melanoma Epidemiology and Prevention

“…The melanocortin-1 receptor (MC1R) gene, which encodes the melanocytestimulating hormone receptor, was identified as the first low-to mediumpenetrance gene associated with melanoma risk [99,232]. 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].…”