Polymorphisms in Nevus-Associated Genes MTAP, PLA2G6, and IRF4 and the Risk of Invasive Cutaneous Melanoma

An evolving hypothesis postulates that melanomas may arise through 'nevus-associated' and 'chronic sun exposure' pathways. We explored this hypothesis by examining associations between nevus-associated loci and melanoma risk across strata of body site and histological subtype. We genotyped 1028 invasive case patients and 1469 controls for variants in methylthioadenosine phosphorylase (MTAP), phospholipase A2, group VI (PLA2G6), and Interferon regulatory factor 4 (IRF4), and compared allelic frequencies globally and by anatomical site and histological subtype of melanoma. Odds-ratios (ORs) and 95% confidence intervals (CIs) were calculated using classical and multinomial logistic regression models. Among controls, MTAP rs10757257, PLA2G6 rs132985 and IRF4 rs12203592 were the variants most significantly associated with number of nevi. In adjusted models, a significant association was found between MTAP rs10757257 and overall melanoma risk (OR = 1.32, 95% Cl = 1.14-1.53), with no evidence of heterogeneity across sites (P(homogeneity) =.52). In contrast, MTAP rs10757257 was associated with superficial spreading/nodular melanoma (OR = 1.34, 95% Cl = 1.15-1.57), but not with lentigo maligna melanoma (OR = 0.79, 95% CI = 0.46-1.35) (P(homogeneity) =.06), the subtype associated with chronic sun exposure. Melanoma was significantly inversely associated with rs12203592 in children (OR = 0.35, 95% Cl = 0.16-0.77) and adolescents (OR = 0.61, 95% CI = 0.42-0.91), but not in adults (P(homogeneity) =.0008). Our results suggest that the relationship between MTAP and melanoma is subtype-specific, and that the association between IRF4 and melanoma is more evident for cases with a younger age at onset. These findings lend some support to the 'divergent pathways' hypothesis and may provide at least one candidate gene underlying this model. Further studies are warranted to confirm these findings and improve our understanding of these relationships.