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

Nature. 2012 Nov 15;491(7424):449-53. doi: 10.1038/nature11624. Epub 2012 Oct 31.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Gene Expression Regulation / drug effects
  • Hair Color / genetics*
  • Indoles / pharmacology
  • Melanins / metabolism
  • Melanoma / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Monophenol Monooxygenase / genetics
  • Peroxidases / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf / genetics
  • Receptor, Melanocortin, Type 1 / genetics
  • Skin Pigmentation / genetics*
  • Sulfonamides / pharmacology
  • Survival Analysis
  • Tumor Cells, Cultured
  • Ultraviolet Rays*


  • Indoles
  • Melanins
  • PLX 4720
  • Protein Kinase Inhibitors
  • Receptor, Melanocortin, Type 1
  • Sulfonamides
  • pheomelanin
  • Peroxidases
  • Monophenol Monooxygenase
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf