Sun exposure indisputably increases the risk of skin cancer. Mouse studies suggest that, in red-haired individuals, genetic factors also contribute through a mechanism that acts independently of exposure to sunlight. See Letter p.449
The most common environmental risk factor for skin cancer is overexposure to sunlight. But is protecting skin from the sun enough to prevent cancer? In this issue, Mitra et al.1 address this question using mice that are genetically similar to humans who have red hair and fair skin or to dark-skinned or albino individuals. They find that the often deadly skin cancer melanoma occurs more frequently in 'redheaded' mice than in the other two groups, owing to mechanisms that are unrelated to exposure to ultraviolet lightFootnote 1.
Colours of skin, eyes and hair vary widely among humans. This variation is controlled by the amount and ratio of two forms of the pigment melanin (the red–yellow pheomelanin and the brown–black eumelanin)2. Both pigment types are produced by melanocytes — cells that are located in the basal layer of the skin epidermis, in hair follicles and in the uvea of the eye. Melanocyte-stimulating hormone binds to the melanocortin 1 receptor (MC1R) on the surface of melanocytes, initiating a biochemical cascade that leads to increased levels of the enzymes required for eumelanin synthesis. Disturbance of the MC1R-mediated signalling pathway reduces total melanin production but increases the relative abundance of pheomelanins — similar to what happens when MC1R is not activated3.
In humans, the MC1R gene can show great variability (polymorphism) in sequence. Certain polymorphisms in this gene are associated with red hair colour (RHC) and so are called RHC variants. These variants result in the loss of functional MC1R, and individuals carrying them often have red hair, fair skin, a tendency to freckle and little ability to tan4.
Caucasians are generally at a higher risk of developing melanoma than are non-Caucasians, and red-haired individuals in particular are more susceptible to melanoma than are those with other hair colours5,6,7 (Fig. 1). Moreover, epidemiological analyses from pooled data sets indicate4 that RHC variants of MC1R are associated with melanoma risk. These observations are not surprising, as red hair is rich in pheomelanin and has little eumelanin. Because eumelanin shields the skin by absorbing ultraviolet (UV) rays8, the skin of red-haired people has a particular tendency to accumulate light-induced damage.
Mitra et al. show that completely avoiding UV rays would not protect red-haired people from melanoma. As an animal model of red-haired individuals, the authors used mice with mutated, non-functional Mc1r, and thus with melanocytes that cannot induce eumelanin synthesis. Whereas control mice had a dark-brown, nearly black coat colour, the Mc1r-mutant mice had golden-yellow coats. A third group of mice expressed non-functional tyrosinase — an enzyme essential for both eumelanin and pheomelanin synthesis — and had white coats, mimicking albinism in humans. These 'white' mice and the 'black' mice possessed intact Mc1r.
Mitra et al. crossed their differently coloured mice with mice that expressed BRafV600E — one of the most common gene mutations in melanoma — in their melanocytes9. BRAFV600E is carried by 40–60% of patients with this cancer10. Furthermore, patients with melanoma who carry RHC variants also have a high frequency of BRAF mutations11, suggesting that BRAF mutations have a role in the development of melanoma in the red-haired population.
When BRafV600E expression was induced in melanocytes, the black mice and their white counterparts developed melanoma only at low rates and after long periods of time. By contrast, more than 50% of the redhead mice developed this cancer within a year of BRafV600E induction, despite being kept in a UV-free environment. Surprisingly, blocking pheomelanin synthesis not only gave the redhead mice a white coat colour, it also reduced the incidence of melanoma among them. These results strongly indicate that the pheomelanin synthesis pathway plays an important part in melanoma development.
Why do redhead mice develop melanoma in the absence of UV light? It seems that redheads carrying RHC variants have a higher risk of melanoma because of intrinsic oxidative DNA damage, in addition to their poor protection from UV. Eumelanin is a strong antioxidant and reduces the accumulation of DNA damage by absorbing reactive oxygen species (ROS). Although pheomelanin may increase cancer risk by generating ROS in response to UV exposure12, this pigment — or its chemical intermediates — can also generate ROS through a mechanism independent of UV radiation13,14. The present paper shows that ROS-mediated damage to both DNA and lipids accumulates more readily in the skins of Mc1r-mutant redhead mice than in Mc1r-mutant white mice, even without UV exposure. Moreover, any such exposure seems to exacerbate oxidative damage selectively in redhead mice1.
Studies are under way to determine whether the increased melanoma risk in redheads is limited only to cancers driven by mutant BRAF, or whether it also applies to other melanoma oncogenes such as NRAS. In addition, it remains to be confirmed whether the risk of this cancer increases in individuals whose red hair is conferred by polymorphisms in other genes of the pigment pathway.
But perhaps the most pertinent question is what can be done, beyond sun protection, to decrease melanoma risk in red-haired, fair-skinned individuals? Destroying all melanin is not an option, because the skin would lack a natural sunshield — eumelanins. Besides, Mitra and co-workers' black mice were relatively well protected against melanoma even though they possessed both pheomelanin and eumelanin. It is conceivable that, in these animals, the abundant eumelanin scavenges pheomelanin-derived ROS. Therefore, it would be of great interest to determine whether topical compounds that induce eumelanin synthesis (such as forskolin), or oral intake of antioxidants, decrease melanoma risk in redheads. Moreover, red-haired individuals should undergo frequent dermatological skin checks, besides avoiding sun exposure.
*This article and the paper under discussion1 were published online on 31 October 2012.
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