Excerpt from “For redheads, skin cancer may be in the genes” by Kate Shaw
It turns out that redheads may be vulnerable to more oxidative DNA damage, even if they stay out of the sun: the researchers found several indicators of DNA damage—lipid peroxide and two cyclopurine levels—were much higher in mice that produced large amounts of pheomelanin. This DNA damage, in turn, contributes to the development of malignant melanoma.
It has long been known that UV radiation causes skin cancer, especially in fair-skinned redheads, but these results suggest that even redheads that stay out of the sun aren’t completely protected from melanoma. The same pigment pathway that gives them their fiery hair and freckles may actually damage their DNA and lead to melanoma, without any help from the sun’s rays. Unfortunately, it’s still unclear how to stop this damage. Experts advise redheads to visit the dermatologist regularly, and suggest that increasing oral antioxidant intake might decrease melanoma risk.
Nature research article behind these finding “An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background“
People with pale skin, red hair, freckles and an inability to tan—the ‘red hair/fair skin’ phenotype—are at highest risk of developing melanoma, compared to all other pigmentation types1. Genetically, this phenotype is frequently the product of inactivating polymorphisms in the melanocortin 1 receptor (MC1R) gene. MC1R encodes a cyclic AMP-stimulating G-protein-coupled receptor that controls pigment production. Minimal receptor activity, as in red hair/fair skin polymorphisms, produces the red/yellow pheomelanin pigment, whereas increasing MC1R activity stimulates the production of black/brown eumelanin2. Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species3, 4, 5. Several observations, however, complicate the assumption that melanoma risk is completely ultraviolet-radiation-dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and ultraviolet radiation signature mutations are infrequently oncogenic drivers6. Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role1, 7. Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAFV600E, into mice carrying an inactivating mutation in the Mc1r gene (these mice have a phenotype analogous to red hair/fair skin humans). We observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet-radiation-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1re/e background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1re/e mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1re/e mouse skin. These data suggest that the pheomelanin pigment pathway produces ultraviolet-radiation-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. Although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.
a, C57BL/6 pigmentation variants with epidermal melanocytes (K14-SCF). From left to right: black (wild type), red (Mc1re/e) and albino (Tyrc/c). b, Genotype of animals used for experimental studies. c, Percentage survival of pigmentation variants not carrying the K14-SCF transgene, that is, no epidermal melanocytes (nblack = 28, nred = 40, nalbino = 48). Pblack–albino = 0.250, Pblack–red = 0.003, Palbino–red = 0.003. d, Percentage survival of pigmentation variants carrying the K14–SCF transgene, that is, epidermal melanocytes (nblack = 49, nred = 77, nalbino = 41). Pblack–albino = 0.103, Pblack–red = 0.009, Palbino–red < 0.0001.