Genetic Mutation that Raises Melanoma Risk IdentifiedAn international group of researchers recently identified a rare genetic mutation associated with an increased risk of melanoma. The mutation, a change in the MITF gene that alters one amino acid in the MITF protein, raises melanoma risk in people with a strong family history of melanoma and also in the general population, the researchers found. The study was published online November 13 in Nature.
Mutations in two genes, CDKN2A and CDK4, are known to increase the risk of familial melanoma, with CDKN2A mutations accounting for nearly 40 percent of familial melanoma cases and CDK4 linked to melanoma risk in a small group of families in which melanoma is common.
In an effort to identify additional genes associated with familial melanoma, lead investigators Dr. Kevin Brown of NCI’s Division of Cancer Epidemiology and Genetics, Dr. Nicholas Hayward of the Queensland Institute of Medical Research, and Dr. Jeffrey Trent of the Translational Genomics Research Institute sequenced the whole genome of several individuals with melanoma from families with multiple cases of the disease. None of the family members had an alteration in the CDKN2A or CDK4 genes.
In one individual, they found a variant in MITF. This gene is involved in numerous important functions in skin cells called melanocytes, the cell type from which melanomas arise. Previous studies have shown that MITF is amplified or mutated in some melanoma tumor samples and overexpressed in others, but none of the studies implicated the gene in risk of developing the disease.
Additional studies of the same individual’s family found the MITF gene variant, called E318K, in several family members who had developed melanoma, though not all. The authors then looked for the MITF variant in samples from two large case-control studies of melanoma involving the general population, as opposed to melanoma-prone families, and found that the E318K variant was carried more frequently by melanoma case subjects than by control subjects. The gene variant was found more often in families with a stronger history of melanoma, multiple primary melanomas, or both, Dr. Brown and his colleagues reported.
The mechanism by which the MITF variant may promote melanoma development is not yet clear, explained Dr. Brown, the study’s senior author. In studies involving cell lines, however, the researchers showed that the variant altered the expression of some of the genes known to be regulated by MITF.
The findings do not change recommendations for regular screenings and other protective behaviors in individuals with a family history of melanoma, Dr. Brown added.
NCI Cancer Bulletin for November 15, 2011 - National Cancer Institute