title: 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 'red hair/fair skin' phenotype--are at highest risk of developing melanoma, compared to all other pigmentation types. 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 eumelanin. Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species. 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 drivers. Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role. Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF(V600E), 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 Mc1r(e/e) background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r(e/e) mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1r(e/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.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Devarati
authors.initials: D
authors.lastname: Mitra
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.forename: Ann
authors.initials: A
authors.lastname: Morgan
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Mai P
authors.initials: MP
authors.lastname: Hoang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lo
authors.forename: Candace R
authors.initials: CR
authors.lastname: Guerrero
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Lennerz
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Robinson
authors.forename: Suprabha P
authors.initials: SP
authors.lastname: Devi
authors.forename: Jillian C
authors.initials: JC
authors.lastname: Vanover
authors.forename: John A
authors.initials: JA
authors.lastname: D'Orazio
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006200:Hair Color / Q000235:genetics*; D007211:Indoles / Q000494:pharmacology; D008543:Melanins / Q000378:metabolism; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D014442:Monophenol Monooxygenase / Q000235:genetics; D010544:Peroxidases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics; D012880:Skin Pigmentation / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
chemical_list: D007211:Indoles; D008543:Melanins; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D044102:Receptor, Melanocortin, Type 1; D013449:Sulfonamides; C018362:pheomelanin; D010544:Peroxidases; D014442:Monophenol Monooxygenase; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf