Melanoma patients with genetic variants in the “red hair gene” have more mutations in their tumours

Guest post by C. Daniela Robles-Espinoza (LIIGH-UNAM, Mexico & Experimental Cancer Genetics, Sanger Institute, UK)

Redheads have heard it too many times now: They know they have to avoid the sun, wear protective clothing and apply sunscreen frequently. They usually burn under the sun and don’t tan which, on top of being painful, can give rise to skin cancer via damage caused to DNA by solar ultraviolet (UV) radiation.

The susceptibility redheads display towards sunlight can be explained by genetics. We usually have two copies of most genes (the exception being those in the X and Y chromosomes in males), and redheads have genetic variants in both copies of a gene called MC1R. The MC1R gene, whose name stands for “melanocortin 1 receptor”, controls the type of melanin that cells produce. Melanin can be made in two forms: A black/brown one, called “eumelanin”, and a red/yellow one, called “phaeomelanin”. Eumelanin is quite good at protecting skin from solar UV radiation, and is the one produced by cells with a MC1R gene without genetic variants. Redheads, with their two copies of MC1R carrying genetic variants, are mostly unable to produce eumelanin and produce phaeomelanin instead, which is not efficient at protecting cells against UV radiation. As a result, they are generally unable to tan and they burn when exposed to UV radiation, which then results in the accumulation of DNA mutations and therefore a higher risk of developing skin cancer.

Redheads have two variant copies of the MC1R gene, whereas dark-haired people might carry one or none.

In a recent study, we have investigated whether the number and types of mutations in melanoma tumours are related to the presence or absence of genetic variants in the MC1R gene (called the MC1R genotype) in melanoma patients. This is interesting because by analysing the types of mutations related to MC1R genotype we can then identify whether they are all caused by sunlight exposure or there are additional mutagenic processes, related to this gene, happening in melanoma tumours. Numbers of mutations are also interesting: Generally, tumours accumulating mutations at a higher rate can evolve and spread faster, but also, it might mean that they are susceptible to novel immunotherapy treatments that target tumours riddled with mutations.

We studied more than 400 tumours from melanoma patients and could make several observations: First, that melanoma tumours from people carrying at least one copy with a variant in the MC1R gene (MC1R variant carriers) have significantly more mutations than people without any of these genetic variants; second, that the increase in the number of sun-associated mutations in tumours from MC1R variant carriers when compared to non-carriers is comparable to the number of mutations gained in an additional 21 years of age; third, that not only the number of sun-associated mutations was increased in MC1R variant carriers but all types of mutations were; and fourth, that these additional, non-UV associated mutations could be due to defects in the ability of MC1R variant carriers to repair DNA.

These results then mean that in addition to redheads, people carrying one copy of MC1R with genetic variants (whom are probably not redheads), need to be careful in the sun as their cells may be accumulating mutations at a higher rate than non-carriers. The calculated increase in the number of mutations then means that, for example, the melanoma tumour of a 40-year old MC1R variant carrier is expected to have as many sun-associated mutations as the tumour from a 61-year old non-carrier. And finally, we found that all types of mutations, not only sun-associated ones, were increased in the tumours from MC1R variant carriers. Possible causes can be defects in the ability of cells with MC1R variants to repair DNA damage or damage caused to DNA by the production of the red pigment. We intend to address these possibilities in future research to learn better why people with these genetic variants have a higher risk of developing melanoma, and hopefully aid in the identification of groups with increased susceptibility to develop this disease.

Fig 1a of Nature Communications doi: 10.1038/ncomms12064
Graph showing the increase in number and type of mutations in MC1R variant carriers (orange box plots) and non-carriers (yellow box plots). Although the number of sun-associated mutations, C>T, is much higher than other mutation types, all mutation types are increased in MC1R variant carriers. Figure taken from Nature Communications doi: 10.1038/ncomms12064

So, in short, the message is clear: Take care in the sun, even if you think you are not susceptible to its mutagenic effects! Not everything may be what it seems, especially when it comes to your genetic makeup.

Reference: Robles-Espinoza, CD et al (2016). Germline MC1R status influences somatic mutation burden in melanoma. Nat Commun 7:12064. doi: 10.1038/ncomms12064.