by ecancer reporter Clare Sansom

People with pale skin and red hair, who burn readily but do not tan after sun exposure, are known to be at the highest risk of developing melanoma.

This increased risk has often been assumed to be entirely due to increased sensitivity to ultraviolet radiation, and people with this pigmentation type are warned to take particular care to avoid sunlight.

Ultraviolet light, however, is an important driver of melanoma development but not the only one. Melanomas, unlike other skin cancers, can occur on unexposed skin and the mutations associated with ultraviolet-associated DNA damage are rarely driver mutations for melanoma development.

A team of researchers led by David Fisher of Massachusetts General Hospital, Charlestown, MA, USA and Meenhard Herlyn of the Wistar Institute, Philadelphia, PA, USA has now made an extensive study of the pathways of melanoma development associated with the red hair / fair skin phenotype using a mouse model.

This phenotype is often associated with polymorphisms in the melanocortin 1 receptor gene MC1R. This gene encodes a G-protein coupled receptor that controls pigment production. When its activity is low, as it is in this light-skinned phenotype, the red-yellow pigment pheomelanin is produced rather than the brown-black eumelanin. 

Fisher, Herlyn and their co-workers produced genetically similar mice to match a range of human skin phenotypes. There were three pigmentation groups: “black” mice with wild type MC1R to mimic dark-skinned humans; “red” mice with a premature MC1R truncation and a high proportion of pheomelanin to eumelanin, mimicking the fair-skinned phenotype; and albino mice that produced no melanin. Some of each phenotype also contained a transgenic stem cell factor that generated melanocytes in the epidermis, as in humans, instead of the dermis.

All mice were then treated with a system in which the oncogenic mutation BRAF^V600E could be expressed specifically in melanocytes, increasing the likelihood of melanoma development.

Initially, BRAF^V600E expression was induced in all six groups of mice and the mice observed without exposure to ultraviolet light or any other known environmental stressors. Both types of “black” mice and, interestingly, both types of albino mice rarely developed melanoma, but over 50% of each type of “red” mice had developed melanoma by the end of the first year. 

All the melanomas observed were similar in morphology and histology, containing little melanin apart from superficial tumour cells in the “black” mice. In most cases, pigmentation in superficial tumour cells could be increased by the application of the adenylate cyclase agonist forskolin, which stimulates skin pigmentation.

Small-molecule inhibitors of BRAF such as PLX4720 were found to inhibit melanoma development in vivo and in vitro, which suggested that the induced V600E mutation in this protein was, indeed, a driver mutation in the development of these tumours.  

The fact that melanomas occurred rarely in albino mice without melanin suggested that it was the presence of pheomelanin, rather than the absence of melanin, that induced melanoma development in the “red” mice.

To test this, the researchers introduced the albino tyrosinase (Tyr^c/c) allele, which prevents melanin formation, into the genetic background of the red mice. These mice remained very largely melanoma-free, further implicating the pheomelanin pathway in melanoma development. Furthermore, the skin of these mice showed significantly less oxidative DNA and lipid damage than that of the normal “red” mice. 

These results suggest that the pheomelanin synthesis pathway that is present in the “red” mice and in people with the red hair / fair skin phenotype can generate oxidative DNA damage independently of ultraviolet light or other stressors, and that this damage contributes to melanoma development. While individuals with this phenotype should still take particular care to avoid excessive exposure to sunlight, this will not be sufficient to decrease their melanoma risk to that of darker-skinned people and further prevention strategies should be sought. 

Reference

Mitra, D., Luo, X., Morgan, A. and 17 others (2012). An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature, published online ahead of print 31 October 2012. doi:10.1038/nature11624