Inherited variation at MC1R and ASIP and association with melanoma-specific survival.
Taylor NJ., Reiner AS., Begg CB., Cust AE., Busam KJ., Anton-Culver H., Dwyer T., From L., Gallagher RP., Gruber SB., Rosso S., White KA., Zanetti R., Orlow I., Thomas NE., Rebbeck TR., Berwick M., Kanetsky PA., GEM Study Group None.
Melanocortin-1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population-based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes 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 of MC1R variants 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). MC1R results 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 haplotype TG near the ASIP locus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma-specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma-specific survival among carriers of two inherited MC1R variants.