Mutation Increases Melanoma Risk In Redheads
August 23, 2013

Got Red Hair? Genetic Mutation Increases Your Melanoma Risk

April Flowers for - Your Universe Online

A person’s hair color and skin tone is determined by their skin pigment. This pigment is influenced by the melanocortin-1 (MC1R) gene receptor. For the world’s redheads – one to two percent of the population – their coloration is accounted for by a mutation in MC1R.

A team of researchers led by Beth Israel Deaconess Medical Center (BIDMC) and Boston University School of Medicine (BUSM) has revealed that the same MC1R mutation responsible for the red hair phenotype also promotes an important cancer-causing pathway, which helps to explain the underlying molecular mechanisms that cause redheads' well-known risk of developing melanoma.

Of all the types of skin cancer, melanoma is the least common and the most lethal. Originating in pigment-producing skin cells called melanocytes, it accounts for 75 percent of all skin-cancer deaths. Scientists believe melanoma is a multi-step process (melanomagenesis) of genetic mutations that increase cell proliferation, cell differentiation and cell death and increase an individual's susceptibility to ultraviolet (UV) radiation. The DNA  in skin cells can be mutated by the two types of UV radiation – UVA and UVB. These mutations lead to melanoma.

"In this current study, we have demonstrated that the mutation MC1R-RHC promotes the PI3K/Akt signaling pathway when a red-haired individual is exposed to UV radiation," explains Wenyi Wei, PhD, an investigator in the Department of Pathology at BIDMC and Associate Professor of Pathology at Harvard Medical School. Implied in breast cancer, ovarian cancer and lung cancer, PI3K/Akt is a well-known cancer-causing pathway.

The scientific team - led by Lixin Wan, PhD, a member of the Wei laboratory at BIDMC and Juxiang Cao, PhD, a member of the Cui lab at BUSM - conducted a series of experiments in both cell cultures and mouse models. Their results revealed that in normal circumstances, MC1R was binding to PTEN, a well-known tumor suppressor gene. This gene acts to safeguard against cancer. Without PTEN, the cancer causing P13K/Akt pathway undergoes elevated signaling.

The study findings also demonstrated that MC1R-RHC mutations found in red-haired individuals lacked this protective mechanism. "As a result, upon UVB exposure, we saw an increased destruction of PTEN in the mutated pigment cells," says Wei. Elevated PI3K/Akt activity in these same MC1R-RHC pigment cells boosted cell proliferation and synchronized with another well-known cancer mutation in the BRAF gene, which is found in nearly 70 percent of human melanomas, to further accelerate cancer development. The researchers note that another research team at Massachusetts General Hospital recently demonstrated that expression of the BRAF gene mutation in the melanocytes of mice carrying a mutated MC1R gene led to a high incidence of invasive melanomas. This supports the findings of the BIDMC study.

"Together, our findings provide a possible molecular mechanism as to why red-haired individuals harboring MC1R mutations are much more susceptible to UV-induced skin damage than individuals with darker skin, resulting in a 10-to100-fold higher frequency of melanoma," says Wei.

The newly discovered link between PTEN and MC1R will be a starting point for future studies. The researchers note that it remains unclear why only MC1R genetic variants linked to the red hair phenotype – but not all MC1R variants – are unable to bind to PTEN following UV exposure.

"We think that MC1R variants, in combination with mutations in the BRAF gene, could be used as markers of an increased risk of developing melanoma," explains Wei. The team suggests that to treat melanoma patients who have both BRAF and MCIR variants, the drug inhibitors that target the PI3K/Akt signaling pathway might be used in combination with Vemurafenib, a drug that targets the BRAF oncogenic protein.

The findings, published online in Molecular Cell, provide new insights for treating and preventing this dangerous type of skin cancer.