A mutation in a gene called MC1R gives redheads their hair color and fair skin. Now a new US study suggests this same mutation triggers a cancer-causing signalling pathway when redheads are exposed to ultraviolet (UV) radiation.
The study authors, from Beth Israel Deaconess Medical Center (BIDMC) and Boston University School of Medicine (BUSM), report their findings in an August 22nd online issue of Molecular Cell.
They hope the study will open new avenues for preventing and treating melanoma. The American Cancer Society says that while melanoma accounts for less than 5% of skin cancer cases, it causes a large majority of skin cancer deaths. Skin cancer as a whole is also “by far the most common” form of all cancer.
In previous work, co-senior author Dr. Rutao Cui, of BUSM’s department of dermatology, showed that MC1R is important for protecting pigment-producing cells called melanocytes from the DNA damage, induced by UV radiation, that can lead to melanoma.
In this new study, Dr. Cui and the other co-senior author, Dr. Wenyi Wei, from BIDMC’s department of pathology and associate professor of pathology at Harvard Medical School, wanted to discover what the underlying mechanisms for this genetic damage might be.
They found that a particular mutation of MC1R, called MC1R-RHC, triggers a well-known cancer-causing signaling pathway in redheads when they are exposed to UV radiation.
To understand more about what was happening, the team then did some tests in cell cultures and live mice.
They discovered that normally MC1R protects against cancer by binding to a tumor suppressor gene called PTEN, the absence of which results in a stronger signal along the cancer-causing P13K/Akt pathway.
And they found the MC1R-RHC mutation, the one that occurs in redheads, lacks this PTEN anti-tumor mechanism.
Dr. Wei says:
“As a result, upon UVB exposure, we saw an increased destruction of PTEN in the mutated pigment cells.”
They found that the higher PI3K/Akt activity of pigment cells carrying the MC1R-RHC mutation, not only boosted tumor growth in its own right, but also by synchronizing with a mutation in the BRAF gene that is found in 70% of human melanomas.
In a separate study, a team at Massachusetts General Hospital recently also found that a BRAF mutation in melanocytes in mice that also carried an MC1R mutation resulted in higher numbers of invasive melanomas.
Dr. Wei says taken together, the two sets of findings show a possible molecular mechanism to explain why redheads with MC1R mutations are more susceptible to UV-induced skin damage and are more than ten times more likely to develop melanoma than people who don’t have fair skin.
“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.”
The researchers point out there are still many unknowns. For instance, why is it that only MC1R mutations in redheads, but not all variants of the gene, fail to bind to PTEN after exposure to UV radiation.
They hope their findings offer a useful starting point for further studies to find the answers.
But in the meantime, they suggest it might be worth exploring whether people with melanoma who carry both BRAF and MC1R mutations, might benefit from drugs that target the PI3K/Akt pathway combined with vemurafenib, a drug that targets the cancer protein coded by BRAF.
In a study published earlier in 2013, researchers in the UK described how, using DNA sequencing, they discovered possible new treatment targets for mucosal melanoma, a rare form of cancer.