Red Hair/Fair Skin Pigmentation Directly Enhances Melanoma Incidence

The red hair/fair skin phenotype is associated with increased risk of melanoma due to polymorphisms in the melanocortin 1 receptor (MC1R) gene. These polymorphisms result in decreased activity of the MC1R cyclic AMP–stimulating G-protein–coupled receptor and production of the red/yellow pheomelanin pigment, which exhibits impaired shielding against UV radiation compared with the black/brown pigment, eumelanin. Mitra and colleagues used mouse pigmentation phenotype models that mimic dark-skinned and red hair/fair skin individuals together with inducible, melanocyte-specific oncogenic BRAF V600E expression to determine whether pigment pathways also contribute to melanomagenesis independent of UV radiation. Elevated pheomelanin production in red–Mc1r^e/e mice, which carry an inactivating mutation in Mc1r, was sufficient to enhance melanoma formation in the absence of environmental stressors such as UV radiation, compared with the low melanoma incidence in wild-type black mice and albino mice that lack all pigment synthesis. Melanomas from each background were histologically similar, amelanotic dermal tumors that exhibited expression of standard melanoma markers, local invasion, the ability to respond to melanocytic differentiation signals, and a dependence on oncogenic BRAF activity. Intriguingly, genetic ablation of pigment synthesis in Mc1r^e/e mice via introduction of the mutant tyrosinase albino allele into this background protected red mice from melanoma, suggesting that pheomelanin or the pathway leading to its synthesis directly promotes tumor formation. This increased melanoma risk is likely driven by augmented reactive oxygen species–mediated damage, as increased oxidative DNA and lipid damage were observed in the skin of red–Mc1r^e/e mice compared with albino–Mc1r^e/e animals. These findings suggest that the intrinsic tumor-promoting function of pheomelanin cooperates with UV radiation–mediated effects to enhance melanoma risk and underscore the need for additional protective strategies in individuals with red hair and fair skin.

Mitra D, Luo X, Morgan A, Wang J, Hoang MP, Lo J, et al. An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature 2012;491:449–53.

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