July 7, 2006

Pigment Gene Affects Risk for Melanoma

Microscopic image of a melanoma Dr. Lance Liotta laboratory, courtesy of NIH's National Cancer Institute.

Melanomas are tumors that arise from the cells that produce skin pigment. While not the most common type of skin cancer, they are the most serious. This year, over 62,000 Americans are expected to be diagnosed with melanoma. Researchers have now uncovered a complex interaction of two genes that dramatically affects the chance of developing melanoma.

The skin around melanomas often has the tell-tale wrinkly, thick appearance brought on by damage from the sun. Ultraviolet radiation from the sun has many effects on skin, including mutating, or changing, cancer-causing genes in skin cells. But not all melanomas are found on skin with obvious chronic sun-induced damage. One gene called BRAF seems particularly important for such melanomas.

Because melanomas on skin without obvious chronic sun-induced damage occur in younger people and have frequent mutations in BRAF, researchers at NIH's National Cancer Institute (NCI) hypothesized that people with these melanomas may have inherited a gene that predisposes them to developing melanomas with BRAF mutations. Caucasian people have a much higher chance than others of developing melanomas on skin that's exposed to the sun, so the researchers thought that one candidate might be the melanocortin-1 receptor (MC1R) gene, which is largely responsible for differences in skin color, or pigmentation. Everyone has two copies of MC1R; one from their mother and one from their father. Some variant forms are responsible for traits such as fair skin, freckling and red hair. But MC1R may do much more than influence pigmentation.

In a collaborative effort by scientists at NCI, the University of California San Francisco and other institutes in the U.S. and Italy, researchers studied the skin surrounding melanomas in 197 Caucasian people and identified those with no or little signs of chronic sun damage. They then sequenced their MC1R genes and BRAF genes from their tumor cells. For comparison, they analyzed the genes in 171 healthy people.

The results were published online in Science on June 29. The non-chronic sun-induced melanomas in people with at least one MC1R variant form had significantly more frequent BRAF mutations. The risk for such melanomas with BRAF mutations was seven times higher for people with one MC1R variant form, and 17 times higher for those with two. In contrast, the people with MC1R variant genes but normal BRAF genes had no higher melanoma risk.

This study shows that MC1R affects melanoma susceptibility in Caucasians by affecting how vulnerable BRAF is to mutation. However, exactly how this relationship works isn't known. Drugs targeting BRAF for melanoma are now in clinical trials. Understanding how other factors like MC1R affect the development of BRAF mutations may help researchers to develop new prevention and therapeutic strategies.

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