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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 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.

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Figure 1: Without ultraviolet radiation, Braf CA red mice have an increased rate of melanoma development relative to black and albino Braf CA animals.
Figure 2: Melanomas on all three pigmentation variants are morphologically similar and exhibit common histologic features.
Figure 3: Tumour cells from a red-Braf CA animal behave like classic BRAF V600E melanomas after cAMP upregulation or BRAF inhibition.
Figure 4: The ultraviolet-radiation-independent propensity of red Braf CA mice to develop melanoma is dependent on pigment production.

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References

  1. Rhodes, A. R., Weinstock, M. A., Fitzpatrick, T. B., Mihm, M. C. J. & Sober, A. J. Risk factors for cutaneous melanoma. A practical method of recognizing predisposed individuals. J. Am. Med. Assoc. 258, 3146–3154 (1987)

    Article  CAS  Google Scholar 

  2. Valverde, P., Healy, E., Jackson, I., Rees, J. L. & Thody, A. J. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nature Genet. 11, 328–330 (1995)

    Article  CAS  Google Scholar 

  3. Rouzaud, F., Kadekaro, A. L., Abdel-Malek, Z. A. & Hearing, V. J. MC1R and the response of melanocytes to ultraviolet radiation. Mutat. Res. 571, 133–152 (2005)

    Article  CAS  Google Scholar 

  4. Wenczl, E. et al. (Pheo)melanin photosensitizes UVA-induced DNA damage in cultured human melanocytes. J. Invest. Dermatol. 111, 678–682 (1998)

    Article  CAS  Google Scholar 

  5. Hill, H. Z. & Hill, G. J. UVA, pheomelanin and the carcinogenesis of melanoma. Pigment Cell Res. 13 (suppl. 8). 140–144 (2000)

    Article  Google Scholar 

  6. Curtin, J. A. et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 2135–2147 (2005)

    Article  CAS  Google Scholar 

  7. Elwood, J. M. & Jopson, J. Melanoma and sun exposure: an overview of published studies. Int. J. Cancer 73, 198–203 (1997)

    Article  CAS  Google Scholar 

  8. Robbins, L. S. et al. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72, 827–834 (1993)

    Article  CAS  Google Scholar 

  9. Halaban, R. et al. Tyrosinases of murine melanocytes with mutations at the albino locus. Proc. Natl Acad. Sci. USA 85, 7241–7245 (1988)

    Article  ADS  CAS  Google Scholar 

  10. Vanover, J. C. et al. Stem cell factor rescues tyrosinase expression and pigmentation in discreet anatomic locations in albino mice. Pigment Cell Melanoma Res. 22, 827–838 (2009)

    Article  CAS  Google Scholar 

  11. Kunisada, T. et al. Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor. J. Exp. Med. 187, 1565–1573 (1998)

    Article  CAS  Google Scholar 

  12. Dankort, D. et al. BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nature Genet. 41, 544–552 (2009)

    Article  CAS  Google Scholar 

  13. Patton, E. E. et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr. Biol. 15, 249–254 (2005)

    Article  CAS  Google Scholar 

  14. Goel, V. K. et al. Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice. Oncogene 28, 2289–2298 (2009)

    Article  CAS  Google Scholar 

  15. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005)

    Article  ADS  CAS  Google Scholar 

  16. Dhomen, N. et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell 15, 294–303 (2009)

    Article  CAS  Google Scholar 

  17. Rae, J. et al. V600EBraf::Tyr-CreERT2::K14-Kitl mice do not develop superficial spreading-like melanoma: keratinocyte kit ligand is insufficient to “translocate” V600EBraf-driven melanoma to the epidermis. J. Invest. Dermatol. 132, 488–491 (2012)

    Article  CAS  Google Scholar 

  18. D'Orazio, J. A. et al. Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature 443, 340–344 (2006)

    Article  ADS  CAS  Google Scholar 

  19. Boni, A. et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 70, 5213–5219 (2010)

    Article  CAS  Google Scholar 

  20. Kadekaro, A. L. et al. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation. FASEB J. 24, 3850–3860 (2010)

    Article  CAS  Google Scholar 

  21. Noonan, F. P. et al. Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment. Nature Commun. 3, 884 (2012)

    Article  ADS  Google Scholar 

  22. Nofsinger, J. B., Liu, Y. & Simon, J. D. Aggregation of eumelanin mitigates photogeneration of reactive oxygen species. Free Radic. Biol. Med. 32, 720–730 (2002)

    Article  CAS  Google Scholar 

  23. Kovacs, D. et al. The eumelanin intermediate 5,6-dihydroxyindole-2-carboxylic acid is a messenger in the cross-talk among epidermal cells. J. Invest. Dermatol. 132, 1196–1205 (2012)

    Article  CAS  Google Scholar 

  24. Wang, J. et al. Quantification of oxidative DNA lesions in tissues of Long-Evans Cinnamon rats by capillary high-performance liquid chromatography−tandem mass spectrometry coupled with stable isotope-dilution method. Anal. Chem. 83, 2201–2209 (2011)

    Article  CAS  Google Scholar 

  25. Wang, Y. Bulky DNA lesions induced by reactive oxygen species. Chem. Res. Toxicol. 21, 276–281 (2008)

    Article  CAS  Google Scholar 

  26. Jaruga, P. & Dizdaroglu, M. 8,5′-Cyclopurine-2′-deoxynucleosides in DNA: mechanisms of formation, measurement, repair and biological effects. DNA Repair (Amst.) 7, 1413–1425 (2008)

    Article  CAS  Google Scholar 

  27. Yuan, B., Wang, J., Cao, H., Sun, R. & Wang, Y. High-throughput analysis of the mutagenic and cytotoxic properties of DNA lesions by next-generation sequencing. Nucleic Acids Res. 39, 5945–5954 (2011)

    Article  CAS  Google Scholar 

  28. Neugut, A. I., Kizelnik-Freilich, S. & Ackerman, C. Black-white differences in risk for cutaneous, ocular, and visceral melanomas. Am. J. Public Health 84, 1828–1829 (1994)

    Article  CAS  Google Scholar 

  29. Green, A. C., Williams, G. M., Logan, V. & Strutton, G. M. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J. Clin. Oncol. 29, 257–263 (2011)

    Article  CAS  Google Scholar 

  30. Huncharek, M. & Kupelnick, B. Use of topical sunscreens and the risk of malignant melanoma: a meta-analysis of 9067 patients from 11 case-control studies. Am. J. Public Health 92, 1173–1177 (2002)

    Article  Google Scholar 

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Acknowledgements

We thank T. Kunisada for generously sharing K14-SCF mice and C. L. Evans for help with mouse skin irradiation. We also thank A. P. Codgill for help with primary tumour cell culture and A. Piris for pathology consultation as well as M. Haigis and Z. Abdel-Malik for discussions. This work was supported by the following grants from the National Institutes of Health 5R01 AR043369-16 (D.E.F.), R01-CA101864 (Y.W.) and F30 ES020663-01 (D.M.), as well as support from the Dr Miriam and Sheldon G. Adelson Medical Research Foundation, the US-Israel Binational Science Foundation, and the Melanoma Research Alliance (D.E.F.).

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Authors

Contributions

D.M. and D.E.F. conceived and planned the project. M.M., M.W.B. and K.M.H. provided the mice carrying the PTEN, BRAFV600E and Tyr-Cre(ER)T2 alleles. D.M. performed the mouse work with help from A.M., J.L., S.P.D. and K.C.R. Histology was performed by D.M., X.L., J.C.V. and J.A.D. with support from D.A.H. Pathological analysis was provided by M.P.H., J.K.L. and M.C.M. In vitro studies were performed by D.M. with help from A.M. and J.L. J.A.W. generated the primary mouse cell line. J.W., C.R.G. and Y.W. collected DNA from mouse skin and performed LC–MS/MS/MS. The manuscript was written by D.M. and D.E.F. All authors discussed the results and commented on the manuscript.

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Correspondence to David E. Fisher.

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The authors declare no competing financial interests.

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Mitra, D., Luo, X., Morgan, A. et al. An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature 491, 449–453 (2012). https://doi.org/10.1038/nature11624

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