No specific association was observed between the type of variant and the number of melanomas, suggesting that the number rather than the type of MC1R variant increases the risk of MPM.
We analyzed 285 melanoma patients of European ancestry for common variation in codon 84 (D84E) of the alpha-MSH receptor 1 gene, which is known to have functional consequences in MC1R protein activity.
MC1R and SLC45A2 variants had additive effects on melanoma risk, and after adjusting for pigmentation characteristics, the risk was persistent, even though both genes had a strong impact on pigmentation.
The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation.
In conclusion, MC1R polymorphisms are a predisposing factor of melanoma in a southern European population with a relatively low incidence of the disease.
Effect modification of the association between MC1R and melanoma risk by phenotypic characteristics and DNA repair capacity was also assessed.All statistical tests were two-sided.
Preliminary genotype/phenotype correlation seems to indicate that other genes involved in the regulation of human pigmentation may mask the recessive action of high-penetrance MC1R alleles, thus determining the low frequency of at-risk phototypes and of incidence and/or penetrance of melanoma in Liguria.
At similar MC1 receptor numbers per cell, alphaMSH increased intracellular cAMP in wild type MC1R transfected melanoma cells, but the cAMP response was compromised in the variant MC1R transfected clones.
Flow cytometry studies showed that melanocortin 1 receptor was expressed in in vitro activated monocytes/macrophages and in the THP-1 monocytic leukaemia line at levels of about 1 in 3 to 1 in 5 of that found in melanomas.
The impact of MC1R variants on risk of melanoma was mediated largely through the action of three common alleles, Arg151Cys, Arg160Trp, and Asp294His, that have previously been associated with red hair, fair skin, and skin sensitivity to ultraviolet light.