Inherited variation atMC1RandASIPand association with melanoma-specific survival

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Abstract

Melanocortin-1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However,MC1Reffects on survival are much less studied. We investigated associations between variation atMC1Rand survival in an international, population-based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study.MC1Rgenotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association ofMC1Rgenotypes with melanoma-specific survival (i.e., death caused by melanoma) and overall survival using COX proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index, and age. In addition, we evaluated haplotypes involving polymorphisms near the Agouti signaling protein gene (ASIP) locus for their impacts on survival. Melanoma-specific survival was inversely associated with carriage ofMC1Rvariants in the absence of consensus alleles compared to carriage of at least one consensus allele (hazard ratio (HR) = 0.60; 95% confidence interval (CI): 0.40, 0.90).MC1Rresults for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma-specific death among carriers of the risk haplotypeTGnear theASIPlocus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most commonGGhaplotype. Similar results were noted for overall survival. Upon examining theASIP TG/TGdiplotype, we observed considerably increased hazard of melanoma-specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most commonGG/GGdiplotype. Our data suggest improved melanoma-specific survival among carriers of two inheritedMC1Rvariants.

What's new?

MC1Rhas important pigmentary biological functions, and inherited variations in the gene are well-known markers of melanoma risk. But whether those variants are also associated with disease survival is unknown. Here, germline variation atMC1Rwas associated with improved melanoma-specific survival in carriers who lacked a consensusMC1Rallele. By contrast, theASIPTG/TG diplotype, which also is known to be associated with melanoma risk, was linked to a 5-fold increase in hazard of death from melanoma. The findings indicate a complex but influential role for pigmentary genetic loci in melanoma outcomes.

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