Pasquali Elena, García-Borrón José C, Fargnoli Maria Concetta, Gandini Sara, Maisonneuve Patrick, Bagnardi Vincenzo, Specchia Claudia, Liu Fan, Kayser Manfred, Nijsten Tamar, Nagore Eduardo, Kumar Rajiv, Hansson Johan, Kanetsky Peter A, Ghiorzo Paola, Debniak Tadeusz, Branicki Wojciech, Gruis Nelleke A, Han Jiali, Dwyer Terry, Blizzard Leigh, Landi Maria Teresa, Palmieri Giuseppe, Ribas Gloria, Stratigos Alexander, Council M Laurin, Autier Philippe, Little Julian, Newton-Bishop Julia, Sera Francesco, Raimondi Sara
Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
Int J Cancer. 2015 Feb 1;136(3):618-31. doi: 10.1002/ijc.29018. Epub 2014 Jun 18.
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.
MC1R基因是皮肤色素沉着的关键调节因子。我们旨在评估在M-SKIP项目中MC1R变异与散发性皮肤黑色素瘤（CM）风险之间的关联，M-SKIP项目是一项关于MC1R、皮肤癌和表型特征的国际汇总分析。数据包括来自17项研究的5160例病例和12119例对照。我们使用随机效应模型计算了9个研究最多的MC1R变异以及与CM相关的变异组合的汇总比值比（SOR）。还进行了按表型特征的分层分析。存在任何主要的MC1R变异都会增加黑色素瘤风险：每个变异的SOR范围从V60L的1.47（95%CI：1.17 - 1.84）到D84E的2.74（1.53 - 4.89）。与野生型受试者相比，任何MC1R变异的携带者发生黑色素瘤的风险高66%（SOR；95%CI：1.66；1.41 - 1.96），且归因于MC1R变异的风险为28%。考虑表型特征时，我们发现MC1R相关的黑色素瘤风险仅在色素沉着较深的白种人中增加：对于没有雀斑、没有红发且皮肤类型为III/IV型的受试者，SOR（95%CI）为3.14（2.06 - 4.80）。我们的研究证明了所有主要的MC1R变异在散发性CM中的重要作用，并表明它们对黑色素瘤风险有直接影响，独立于携带者的表型特征。这对于评估预防策略尤为重要，预防策略可能针对具有MC1R变异的色素沉着较深的白种人以及色素沉着浅、皮肤白皙的受试者。
