Red Hair, Light Skin, and UV-Independent Risk for Melanoma Development in Humans

A key gene that regulates pigmentation in humans is the melanocortin-1-receptor gene (MC1R;O M I M155555), which encodes a 7-transmembrane G-protein-coupled receptor that regulates adenosine 3′, 5′ cyclic monophosphate (cAMP) levels in melanocytes.MC1R is activated by melanocyte stimulating hormone (MSH), which is secreted by UVirradiated keratinocytes in the "tanning" response.1 MC1R loss of function is one means of generating light skin that likely facilitates vitamin D biosynthesis.This plausibly provided an evolutionary selective advantage in preventing lethal vitamin D deficiency at high latitudes.Negative selective pressure may have arisen at low latitudes (higher UV intensity) owing to photolysis of vital factors such as folate or potentially increased skin cancer risk in lightly pigmented individuals.In individuals with Fitzpatrick skin type 1, light skin, and red hair, more than 80% bear a dysfunctional variant in both MC1R alleles. 2 MC1R signaling upregulates tyrosinase, the strong enzymatic activity of which results in synthesis of brown-black eumelanin.In contrast, loss-of-function MC1R variants produce lower cAMP and tyrosinase levels, which induce formation of pheomelanin pigment.Pheomelanin not only lacks efficient UV shielding capacity, but it (or its biosynthetic intermediates) actively induces formation of reactive oxygen species (ROS) as well as DNA damage.3 About 60% of persons with skin type 2 carry a single loss-of-function MC1R allele, while fewer than 20% of all individuals with skin type 3 or higher show 1 dysfunctional allele. 2 Melanoma incidence has risen over 30-fold in the last century.4 Among individuals of European descent in the United States, melanoma incidence is about 3 times higher than in Asians and about 15 times higher than in individuals from South America and Africa.5 Because melanin levels largely influence melanoma risk, studies have examined the effect of yellow-red pheomelanin and brown-black eumelanin on this melanoma risk.6 While UV is a key contributor to melanoma risk, with numerous UV signature mutations typically found throughout the melanoma genome, certain studies have suggested that additional mechanisms may contribute to melanoma risk.One of the suggested contributors is pheomelanin.In a preclinical model, Mitra and colleagues 7 studied mice carrying a conditional allele of BRAF V600E that on a genetically black background (wild-type Mc1r) produces benign nevi.When it was crossed onto an Mc1r loss-of-function background, about 50% of mice developed invasive melanomas.To investigate whether the melanoma risk was related to the pheomelanin pigment in the Mc1r loss-of-function gene (or a different biological consequence of having low cAMP signaling), the researchers