MC1R variants increased the risk of sporadic cutaneous melanoma in darker‐pigmented Caucasians: A pooled‐analysis from the M‐SKIP project

The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M‐SKIP project, an international pooled‐analysis on MC1R, skin cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 controls from 17 studies. We calculated a summary odds ratio (SOR) for the association of each of the nine most studied MC1R variants and of variants combined with CM by using random‐effects models. Stratified analysis by phenotypic characteristics were also performed. Melanoma risk increased with presence of any of the main MC1R variants: the SOR for each variant ranged from 1.47 (95%CI: 1.17–1.84) for V60L to 2.74 (1.53–4.89) for D84E. Carriers of any MC1R variant had a 66% higher risk of developing melanoma compared with wild‐type subjects (SOR; 95%CI: 1.66; 1.41–1.96) and the risk attributable to MC1R variants was 28%. When taking into account phenotypic characteristics, we found that MC1R‐associated melanoma risk increased only for darker‐pigmented Caucasians: SOR (95%CI) was 3.14 (2.06–4.80) for subjects with no freckles, no red hair and skin Type III/IV. Our study documents the important role of all the main MC1R variants in sporadic CM and suggests that they have a direct effect on melanoma risk, independently on the phenotypic characteristics of carriers. This is of particular importance for assessing preventive strategies, which may be directed to darker‐pigmented Caucasians with MC1R variants as well as to lightly pigmented, fair‐skinned subjects. What's new? The MC1R gene regulates production of the protective skin pigment eumelanin in response to sun exposure. In this study, the authors found that carriers of any of nine MC1R variants had a substantially increased risk of developing sporadic CM. Surprisingly, however, this increased risk was significant only for darker‐pigmented Caucasians. This information is important for targeted preventive strategies, as fair‐skinned people have previously been assumed to be at greatest risk for CM.