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Gene Changes Linked to Most Common Form of Melanoma

Summary: A new study may shed some light on why some people develop melanoma on parts of their bodies that don't get much sun. Researchers say these people often have a variation in a gene called MC1R which makes the skin sensitive to small amounts of any type of ultraviolet (UV) light.

Why it's important: Melanoma can be a deadly cancer that often strikes people in early adulthood and middle age. In 2006, an estimated 62,190 people in the United States will be diagnosed with melanoma and nearly 8,000 people will die from this cancer. Some people seem especially prone to melanoma. If doctors could identify who these people are, they might be able to take steps to reduce their risk. There are no tests available yet, but the information from this study may be a step in that direction.

What's already known: Most, though not all, melanomas are triggered by exposure to UV light, from the sun or other sources like tanning booths. But different types of melanomas seem to be linked to different amounts of UV exposure.

The least common type, which develops on the palms of the hands, soles of the feet, and internal surfaces such as the vagina and mouth, are obviously not caused by sun exposure. But high UV exposure is needed for another more common type, which typically occurs in people in their 50s and 60s in highly sun-exposed areas like the face and neck. Often, there is a lot of sun damage to the skin associated with these melanomas.

The most common type of melanoma develops on the trunk and legs of fair skinned people, who are often in their 30s and 40s. Although some UV exposure is necessary for the melanoma to develop, these areas do not get a lot of sun exposure, and the skin does not show signs of sun damage. Yet these people are prone to melanoma, which is hard to prevent because a small amount of UV exposure may be all that is needed to initiate the cancer.

These 3 types of melanomas have distinct patterns of chromosome abnormalities. The most common type, found in fair skinned people on the trunk and legs, often contains a mutation in the gene called BRAF. This is a mutation that has developed only in the cancer cells, not in other cells of the body, so it wasn't something the person inherited. Scientists think that the mutation in the BRAF gene may be responsible for the uncontrolled growth of the melanoma.

How this study was done: A team of researchers from the United States, Germany, and Italy wanted to know what makes the people with the BRAF-containing melanomas so sensitive to relatively little sun exposure, and why they develop their melanoma at such a young age. To answer this, the researchers looked at a gene called MC1R, or melanocortin-1-receptor.

MC1R helps cells make the brown pigment in our skin when we tan. Each person normally has 2 copies of this gene in each cell. In some people, either one or both copies of this gene have certain changes (called variations) that cause very fair skin, freckling, and red hair -- all of which make people more susceptible to melanoma. The researchers looked for other variations that might also make people susceptible to developing melanoma.

They examined the MC1R genes in blood samples from melanoma patients and also checked whether or not there were BRAF mutations in their melanomas. The patients were divided into 3 groups. People with 2 normal MC1R genes were placed in one group. People with one normal gene and one variation-containing gene were in a second group, and those with 2 variation-containing genes were put into the third group.

What was found: People who had 2 normal MC1R genes generally did not have BRAF mutations in their cancer. These people also generally had the kind of melanomas linked to heavy sun damage. People with a variation in only 1 of the 2 MC1R genes were 7 times more likely to have a BRAF mutation. And those with variations in both MC1R genes were 17 times more likely to have BRAF mutations. Most of the people in these last 2 groups had melanomas in non-sun damaged areas such as the trunk or legs.

The bottom line: Although the researchers don't know why these changes in MC1R cause the BRAF mutation and melanoma, they provide a clue for spotting the most susceptible people. They also help us understand why some melanomas develop on the trunk and legs of people who haven't had much sun exposure, while it takes a lot of sun exposure to cause melanomas in other people. Still, the researchers feel there is much more to learn before we can understand why melanoma develops.

Citation: "MC1R Germline Variants Confer Risk for BRAF-Mutant Melanoma." Published online in Sciencexpress www.sciencexpress.org June 29, 2006. First author: Maria Teresa Landi, National Cancer Institute.