Link Between Genetic Mutation, Melanoma Discovered
November 14, 2011

Link Between Genetic Mutation, Melanoma Discovered

An international team of researchers has discovered a new genetic mutation that they report appears to increase the risk of the deadliest form of skin cancer, malignant melanoma.

The study, which was led by medical experts from Massachusetts General Hospital (MGH), Queensland Institute of Medical Research (QIMR), and Translational Genomics Research Institute (TGen), revealed a mutation "in the gene encoding MITF, a transcription factor that induces the production of several important proteins in melanocytes, the cells in which melanoma originates."

Previous research had suggested that MITF could act as a melanoma oncogene. This new study, which has been published online at the website of the journal Nature, has pinpointed a mechanism by which mutation of the gene could increase a person's risk for contracting malignant melanoma.

"We previously knew that MITF is a master regulator for production of the pigment melanin; and several years ago we identified a chemical modification, called sumoylation, that represses MITF activity," co-senior author Dr. David Fisher, the chief of Dermatology at MGH and the director of the hospital's Cutaneous Biology Research Center, said in a statement. "The currently discovered mutation appears to block sumoylation of MITF, and the resulting overactivity of MITF significantly increases melanoma risk."

According to the MGH press release, the researchers began their work by sequencing the genome of a melanoma patient from a family in which eight cases of the cancer had been reported across three different generations. That genome contained neither of the identified high-risk mutations, and while studying generic variants, they focused on an MITF mutations, since it had been previously identified as a potential melanoma oncogene.

They then expanded their research, analyzing genotyped samples from over 15,000 subjects from the UK and Australia. They discovered that the mutation that they had located occurred more frequently in those with melanoma than in healthy subjects, and was reportedly even more common in families where there were two or more people who had contracted melanoma.

"This MITF variant doubles the background risk for melanoma, which is approximately the same risk increase conferred by severe sunburns," co-senior author Dr. Hensin Tsao, representing MGH Dermatology, said. "Furthermore, documenting this moderate level of risk required thousands of cases and controls worldwide, a testament to the unique collaborative nature of this study and the potential utility of next-generation sequencing for gene discovery."

"We now need to better understand exactly how this mutation causes melanocytes to become cancerous," Fisher added. "That information might help us discover other oncogenes as well as find treatment strategies to block the cancer-promoting activity and kill melanoma cells."

Joining Fisher and Tsao as authors on the study are Satoru Yokoyama of the MGH Cutaneous Biology Research Center; Susan Woods, Glen Boyle, Lauren Aoude, and Stuart MacGregor of QIMR in Australia; and Victoria Zismann of TGen in Phoenix, Arizona. Furthermore, other co-senior authors are Jeffrey Trent of TGen, Nicholas Hayward of QIMR, and Kevin Brown of the National Cancer Institute.


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