Because melanomas on skin areas with few signs of chronic sun-induced damage occur in younger people and exhibit frequent mutations in BRAF, the researchers hypothesized that there were inherited genetic factor(s) that predispose to the development of these melanomas with BRAF mutations. An interesting candidate for this genetic risk factor was the MC1R gene.

To determine if there was an association between inherited variant forms of MC1R and the development of BRAF-mutant melanoma, the researchers studied the skin surrounding the melanomas in 85 patients from the Bufalini Hospital of Cesena, Italy, and 112 patients from the Department of Dermatology at the University of California, San Francisco, and identified subjects with no or little signs of chronic sun damage. They then sequenced MC1R genes in normal cells and BRAF in tumor cells and found that BRAF mutations were more frequent in non-chronic sun-induced melanoma cases with hereditary genetic variant forms of MC1R.


By categorizing patients into two groups, those with no variant forms of MC1R versus those who had at least one variant, the scientists found that BRAF mutations were six to 13 times more frequent in those with at least one MC1R variant form. Looking more closely, the investigators found that the risk for melanoma with BRAF mutations rose with increasing number of MC1R variant forms. Comparing data from melanoma patients and healthy controls, the risk for melanomas with BRAF mutations increased from seven times for individuals with one MC1R variant form, to 17 times for those with two variant forms, when compared with individuals with the standard MC1R.

The study results show that normal variations in the MC1R gene in Caucasians have a very specific effect on melanoma susceptibility. Additional inherited factors that affect susceptibility may also be present, but they have yet to be discovered. The mechanism by which variant forms of the MC1R gene facilitate development of melanomas with BRAF mutations is currently unknown, said Landi. One possibility is that people with MC1R variant forms and variable pigmentation generate more reactive chemicals in their cells as a result of the ultraviolet exposure in sunlight. These reactive chemicals can induce mutations, like those in the BRAF gene, which may lead to cancer.

Clinical trials for melanoma using pharmaceutical drugs directed against the BRAF gene are ongoing. Knowledge of predisposing factors in the development of BRAF mutations, such as MC1R, might aid prevention and therapeutic strategies in the future.

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