The D84E variant of the α-MSH receptor 1 gene is associated with cutaneous malignant melanoma early onset

Summary Background Alpha-melanocyte-stimulating hormone receptor 1 (MC1R) has an important role in skin pigmentation and variants of the gene have been established as independent risk factors for susceptibility to cutaneous malignant melanoma. Objective To explore whether variants of the gene also influence the onset of the disease. Methods We analyzed 285 melanoma patients of European ancestry for common variation in codon 84 (D84E) of the α-MSH receptor 1 gene, which is known to have functional consequences in MC1R protein activity. Results The mean age difference at diagnosis between MC1R 84E carriers and non-carriers was 9 years (95% confidence interval [CI]: 2–17; p = 0.012), with 84E non-carrier patients being older. After adjusting for gender, Clark's level, phototype, eyes and hair colour, the risk for cutaneous malignant melanoma at any age was 2.07 times higher (95% CI: 1.21–3.52; p = 0.008) among MC1R 84E carriers. Enrolment criteria, geographical origin, Clark's levels and Breslow's indexes were similar between MC1R 84E carriers and non-carriers. Further analyses based on the Clark level and Breslow's index, both indicative for cancer invasion, reasonably supported an unbiased selection of patients during the study enrolment. Additional exon re-sequencing of the cyclin-dependent kinase inhibitor 2A ( CDKN2A ) gene in MC1R 84E carriers ruled out the presence of high penetrance mutations that have previously been associated with early onset of the disease. Conclusion Although our findings need to be confirmed by independent and larger studies we have described for the first time the association of D84E variant of the α-MSH receptor 1 gene as an independent risk factor for an earlier onset of cutaneous malignant melanoma.