MC1R genotypes and risk of melanoma before age 40 years: A population-based case-control-family study

The contribution of melanocortin-1 receptor (MC1R) gene variants to the development of early-onset melanoma is unknown. Using an Australian population-based, case-control-family study, we sequenced MC1R for 565 cases with invasive cutaneous melanoma diagnosed between ages 18 and 39 years, 409 unrelated controls and 518 sibling controls. Variants were classified a priori into "R" variants (D84E, R142H, R151C, I155T, R160W, D294H) and "r" variants (all other nonsynonymous variants). We estimated odds ratios (OR) for melanoma using unconditional (unrelated controls) and conditional (sibling controls) logistic regression. The prevalence of having at least one R or r variant was 86% for cases, 73% for unrelated controls and 81% for sibling controls. R151C conferred the highest risk (per allele OR 2.57, 95% confidence interval 1.86-3.56 for the case-unrelated-control analysis and 1.70 (1.12-2.60) for the case-sibling-control analysis). When mutually adjusted, the ORs per R allele were 2.23 (1.77-2.80) and 2.06 (1.47-2.88), respectively, from the two types of analysis, and the ORs per r allele were 1.69 (1.33-2.13) and 1.25 (0.88-1.79), respectively. The associations were stronger for men and those with none or few nevi or with high childhood sun exposure. Adjustment for phenotype, nevi and sun exposure attenuated the overall log OR for R variants by approximately 18% but had lesser influence on r variant risk estimates. MC1R variants explained about 21% of the familial aggregation of melanoma. Some MC1R variants are important determinants of early-onset melanoma. The strength of association with melanoma differs according to the type and number of variants.