An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background
Open accessAbstract
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.
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Braf-mutant mice carrying the pheomelanin-associated Mc1re/e allele develop 10 times more spontaneous melanomas.
“Braf-mutant mice develop 10 times more spontaneous melanomas if they carry the pheomelanin-associated Mc1re/e allele (4).”
From Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure (2015) · cites this paper as [4]
The paper’s results passage (labelled Abstract; page unavailable) reports that red Mc1re/e Braf-mutant mice developed melanomas without UV exposure at a higher rate than black Braf-mutant mice, with more than 50% of red mice having tumors after one year. Our copy does not give a tenfold comparison, so the precise magnitude attributed to the paper is not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSynthesis of pheomelanin, in the absence of eumelanin, in recessive yellow mice harboring a loss-of-function mutation in mc1r and the V600E mutation in Braf results in excessive oxidative DNA damage and lipid peroxidation that induce spontaneous melanoma tumor formation.
“Moreover, the synthesis of pheomelanin, in the absence of eumelanin, in recessive yellow mice harboring a loss-of-function mutation in melanocortin 1 receptor ( mc1r) and the V600E mutation in Braf, results in excessive oxidative DNA damage and lipid peroxidation that induce spontaneous melanoma tumor formation [ 10 ].”
From Differential Induction of Reactive Oxygen Species and Expression of Antioxidant Enzymes in Human Melanocytes Correlate with Melanin Content: Implications on the Response to Solar UV and Melanoma Susceptibility (2022) · cites this paper as [10]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredPheomelanin is photolabile, a prooxidant, and potentially oncogenic.
“Pheomelanin, on the other hand, is photolabile, a prooxidant, and is potentially oncogenic [ 8 , 10 ].”
From Differential Induction of Reactive Oxygen Species and Expression of Antioxidant Enzymes in Human Melanocytes Correlate with Melanin Content: Implications on the Response to Solar UV and Melanoma Susceptibility (2022) · cites this paper as [10]
The Abstract says pheomelanin amplifies UVA-induced reactive oxygen species and that its synthesis pathway is associated with oxidative damage and may contribute to melanoma. It does not say pheomelanin is photolabile; weak UV shielding and UVA-related damage do not establish that property. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPheomelanin is a strong prooxidant and, on its own, is oncogenic in the absence of any exogenous carcinogen.
“These results led to the conclusion that pheomelanin is a strong prooxidant and, on its own, is oncogenic in the absence of any exogenous carcinogen [ 10 ].”
From Differential Induction of Reactive Oxygen Species and Expression of Antioxidant Enzymes in Human Melanocytes Correlate with Melanin Content: Implications on the Response to Solar UV and Melanoma Susceptibility (2022) · cites this paper as [10]
The paper reports greater oxidative DNA and lipid damage in red mice than in albino mice and melanoma development without UV exposure (Abstract; page unavailable). But the melanoma experiments used mice with introduced oncogenic BRAF activation, and the authors attribute the effect to the pheomelanin synthesis pathway—not definitively to pheomelanin itself. Thus the source does not establish that pheomelanin is a strong prooxidant or is oncogenic on its own. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA study on recessive yellow mice harboring a loss-of-function mutation in mc1r and the activating Braf V600E mutation found that pheomelanin generated extensive reactive species, oxidative DNA damage, and lipid peroxidation and resulted in spontaneous melanoma tumor formation.
“A study on recessive yellow mice harboring a loss-of-function mutation in mc1r and the activating Braf V600E mutation found that pheomelanin, exclusively synthesized by melanocytes in this model [ 61 ], generated extensive reactive species, oxidative DNA damage, and lipid peroxidation and resulted in spontaneous melanoma tumor formation [ 10 ].”
From Differential Induction of Reactive Oxygen Species and Expression of Antioxidant Enzymes in Human Melanocytes Correlate with Melanin Content: Implications on the Response to Solar UV and Melanoma Susceptibility (2022) · cites this paper as [10]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
The double nature of melanin would explain the apparent cancer-facilitating effects of melanin seen in mice and human epidemiology.
“This double nature would explain the apparent cancer-facilitating effects of melanin seen in mice and in human epidemiology (2-4, 6).”
From Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure (2015) · cites this paper as [4]
Increased lipid peroxidation in L melanocytes suggests that low levels of eumelanin allow for the prooxidant effects of pheomelanin, which increase the oxidative damage and lipid peroxidation.
“Increased lipid peroxidation in L melanocytes suggests that low levels of eumelanin allow for the prooxidant effects of pheomelanin, which increase the oxidative damage and lipid peroxidation, consistent with the findings by Mitra et al. [ 10 ].”
Pheomelanins have been implicated in UV-radiation-independent carcinogenic contributions to melanomagenesis by inducing oxidative DNA damage.
“Pheomelanins have also been implicated in UV-radiation-independent carcinogenic contributions to melanomagenesis by inducing oxidative DNA damage [65,66,67].”
From “Fifty Shades” of Black and Red or How Carboxyl Groups Fine Tune Eumelanin and Pheomelanin Properties (2016) · cites this paper as [65]
In vivo, UVB exposure accelerates melanomagenesis independently of MC1R mutation status and pigmentation.
“In vivo, however, UVB exposure accelerates melanomagenesis independent of MC1R mutation status and pigmentation47, suggesting that UVB-induced melanomagenesis does not require the pigmentation and MC1R signaling response.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [47]
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- Authors
- Mitra, D., Luo, X., Morgan, A., Wang, J., Hoang, M. P., Lo, J., Guerrero, C. R., Lennerz, J. K., Mihm, M. C., Wargo, J. A., Robinson, K. C., Devi, S. P., Vanover, J. C., D’Orazio, J. A., McMahon, M., Bosenberg, M. W., Haigis, K. M., Haber, D. A., Wang, Y., & Fisher, D. E.
- Affiliations
- Massachusetts General Hospital (US)
- Harvard University (US)
- University of California, Riverside (US)
- Universität Ulm (DE)
- University of Kentucky (US)
- University of California, San Francisco (US)
- Yale University (US)
- Corresponding author
- Fisher, David E.
- ORCID
- Venue
- Nature
- Published
- 2012-10-31
- Volume
- 491
- Issue
- 7424
- Pages
- 449-453
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3521494
- OpenAlex
- W2109511835
- Cited by
- 497
- References
- 30
- Citations by year
- 2026: 16 · 2025: 25 · 2024: 26 · 2023: 25 · 2022: 36 · 2021: 34 · 2020: 40 · 2019: 40 · 2018: 39 · 2017: 42 · 2016: 46 · 2015: 34 · 2014: 52 · 2013: 38 · 2012: 3
- FWCI
- 16.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1f30es020663-01)
- National Cancer Institute (R01CA101864, R01CA131075, R01CA129933, R01CA176839)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Environmental Health Sciences (F30 ES020663, F30 ES020663-01)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR043369)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- melanoma, MC1R, pheomelanin, eumelanin, BRAF V600E mutation, oxidative DNA damage, oxidative DNA damage repair, skin pigmentation, melanoma susceptibility, mouse model, skin cancer prevention, sun protection, reactive oxygen species
- MeSH terms
- Animals, Gene Expression Regulation, Hair Color, Indoles, Melanins, Melanoma, Mice, Inbred C57BL, Peroxidases, Skin Pigmentation, Sulfonamides, Tumor Cells, Cultured, Monophenol Monooxygenase, Ultraviolet Rays, Survival Analysis, Receptor, Melanocortin, Type 1, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Cell Proliferation, Mice
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