An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background

Abstract

People with pale skin, red hair, freckles, and an inability to tan—the “redhair/fairskin” 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 cAMP stimulating G-protein coupled receptor that controls pigment production. Minimal receptor activity, as in redhair/fairskin polymorphisms, produces red/yellow pheomelanin pigment, while increasing MC1R activity stimulates production of black/brown eumelanin2. Pheomelanin has weak UV shielding capacity relative to eumelanin and has been shown to amplify UVA-induced reactive oxygen species (ROS) 3–5. Several observations, however, complicate the assumption that melanoma risk is completely UV dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and UV signature mutations are infrequently oncogenic drivers6. While linkage of melanoma risk to UV exposure is beyond doubt, UV-independent events are also likely to play a significant role1,7. Here, we introduced into mice carrying an inactivating mutation in the Mc1r gene (who exhibit a phenotype analogous to redhair/fairskin humans), a conditional, melanocyte-targeted allele of the most commonly mutated melanoma oncogene, BRafV600E. We observed a high incidence of invasive melanomas without providing additional gene aberrations or UV exposure. To investigate the mechanism of UV-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r e/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 UV-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. While UV protection remains important, additional strategies may be required for optimal melanoma prevention.

Melanocytes and Oxidative Stress

“…In those persons with fair skin and red hair, specific mutations at the MC1R gene are responsible for the switch from eumelanin to phaeomelanin, inducing increased oxidative stress and higher risk of melanoma [35,36]. In a similar manner, it was demonstrated that recessive yellow mice with loss-of-function MC1R were developing more invasive melanoma than their albino counterparts [75].…”

Comprehensive Assessment of Oxidatively Induced Modifications of DNA in a Rat Model of Human Wilson's Disease

“…Byproducts of LPO could react with DNA to generate exocyclic adducts, including 1,N 6 -etheno-2Ј-deoxyadenosine (dA) and 1,N 2 -etheno-2Ј-deoxyguanosine (dG) (5,6). Multiple lines of evidence showed that these DNA lesions in mammalian cells, tissues and blood may serve as potential biomarkers of oxidative stress (7)(8)(9)(10)(11)(12)(13)(14).…”

Melanoma genotypes and phenotypes get personal

“…This demonstrates complexion matters, as the oxidative-damage-repair pathways may have a role in the pathogenesis of MM. 13 In the next section, new studies related to the role of sunlight and MM are reviewed.…”

“…12 The role for ROS in generating DNA mutations in MM, regardless of the exposure to sunlight, has gained momentum due to recent findings with red-hairbearing mice (so-called ginger mice), in which pheomelanin predominates over eumelanin. 13 Using genomically distinct strains of mice, it was demonstrated that there might be an ultraviolet radiation-independent pathway to MM carcinogenesis. The pigmentation phenotype resulting from the ratio of pheomelanin to eumelanin reflects polymorphisms in the melanocortin 1 receptor (MC1R) gene and in tyrosinase gene activity that can lead to a UV-radiation-independent carcinogenesis in mice.…”