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. 2015 Feb 1;136(3):618-31.
doi: 10.1002/ijc.29018. Epub 2014 Jun 18.

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

Elena Pasquali  1 , José C García-Borrón, Maria Concetta Fargnoli, Sara Gandini, Patrick Maisonneuve, Vincenzo Bagnardi, Claudia Specchia, Fan Liu, Manfred Kayser, Tamar Nijsten, Eduardo Nagore, Rajiv Kumar, Johan Hansson, Peter A Kanetsky, Paola Ghiorzo, Tadeusz Debniak, Wojciech Branicki, Nelleke A Gruis, Jiali Han, Terry Dwyer, Leigh Blizzard, Maria Teresa Landi, Giuseppe Palmieri, Gloria Ribas, Alexander Stratigos, M Laurin Council, Philippe Autier, Julian Little, Julia Newton-Bishop, Francesco Sera, Sara Raimondi; M-SKIP Study Group
Collaborators, Affiliations

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

Elena Pasquali et al. Int J Cancer. .

Abstract

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.

Keywords: genetic epidemiology; melanocortin-1 receptor; melanoma; meta-analysis.

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Conflict of interest statement

Author’s disclosures of potential conflicts of interest: none for all authors.

Figures

Figure 1
Figure 1
Study-specific and pooled-Odds Ratio (OR) with 95% Confidence Intervals (CI) for the association between cutaneous melanoma and MC1R variants (A) V60L, (B) D84E, (C) V92M, (D) R142H, (E) R151C, (F) I155T, (G) R160W, (H) R163Q, (I) D294H. Reference category for each variant comprises WT subjects
Figure 1
Figure 1
Study-specific and pooled-Odds Ratio (OR) with 95% Confidence Intervals (CI) for the association between cutaneous melanoma and MC1R variants (A) V60L, (B) D84E, (C) V92M, (D) R142H, (E) R151C, (F) I155T, (G) R160W, (H) R163Q, (I) D294H. Reference category for each variant comprises WT subjects
Figure 1
Figure 1
Study-specific and pooled-Odds Ratio (OR) with 95% Confidence Intervals (CI) for the association between cutaneous melanoma and MC1R variants (A) V60L, (B) D84E, (C) V92M, (D) R142H, (E) R151C, (F) I155T, (G) R160W, (H) R163Q, (I) D294H. Reference category for each variant comprises WT subjects
Figure 1
Figure 1
Study-specific and pooled-Odds Ratio (OR) with 95% Confidence Intervals (CI) for the association between cutaneous melanoma and MC1R variants (A) V60L, (B) D84E, (C) V92M, (D) R142H, (E) R151C, (F) I155T, (G) R160W, (H) R163Q, (I) D294H. Reference category for each variant comprises WT subjects
Figure 1
Figure 1
Study-specific and pooled-Odds Ratio (OR) with 95% Confidence Intervals (CI) for the association between cutaneous melanoma and MC1R variants (A) V60L, (B) D84E, (C) V92M, (D) R142H, (E) R151C, (F) I155T, (G) R160W, (H) R163Q, (I) D294H. Reference category for each variant comprises WT subjects
Figure 1
Figure 1
Study-specific and pooled-Odds Ratio (OR) with 95% Confidence Intervals (CI) for the association between cutaneous melanoma and MC1R variants (A) V60L, (B) D84E, (C) V92M, (D) R142H, (E) R151C, (F) I155T, (G) R160W, (H) R163Q, (I) D294H. Reference category for each variant comprises WT subjects
Figure 1
Figure 1
Study-specific and pooled-Odds Ratio (OR) with 95% Confidence Intervals (CI) for the association between cutaneous melanoma and MC1R variants (A) V60L, (B) D84E, (C) V92M, (D) R142H, (E) R151C, (F) I155T, (G) R160W, (H) R163Q, (I) D294H. Reference category for each variant comprises WT subjects
Figure 1
Figure 1
Study-specific and pooled-Odds Ratio (OR) with 95% Confidence Intervals (CI) for the association between cutaneous melanoma and MC1R variants (A) V60L, (B) D84E, (C) V92M, (D) R142H, (E) R151C, (F) I155T, (G) R160W, (H) R163Q, (I) D294H. Reference category for each variant comprises WT subjects
Figure 1
Figure 1
Study-specific and pooled-Odds Ratio (OR) with 95% Confidence Intervals (CI) for the association between cutaneous melanoma and MC1R variants (A) V60L, (B) D84E, (C) V92M, (D) R142H, (E) R151C, (F) I155T, (G) R160W, (H) R163Q, (I) D294H. Reference category for each variant comprises WT subjects
Figure 2
Figure 2
Attributable risks* in the population for cutaneous melanoma according to each MC1R variant (percentages with 95% confidence intervals). Reference category for each variant comprises WT subjects
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