Melanoma grows "addicted" to novel oncogene

Scientists from the Dana-Farber Cancer Institute and the Broad Institute have found that abnormal amplification of the gene encoding MITF (microphthalmia-associated transcription factor) may underlie at least some forms of metastatic melanoma. Their discovery also suggests MITF as a novel target for drug discovery and development for this deadly disease.

"By pinpointing the abnormally multiplied MITF oncogene, we may be able to develop better diagnostic and prognostic tools as well as provide a target for highly specific therapies for metastatic melanoma patients who have this overcopied gene," says senior author Bill Sellers, who also holds an appointment with the Broad Institute of Harvard and MIT and with Harvard Medical School.

Reporting their findings in the July 7 issue of the journal Nature, the researchers describe using single nucleotide polymorphism (SNP) array technology to identify regions of chromosomes where genes were either left out or abnormally multiplied — mistakes often associated with cancer. In studying cells from primary and metastatic melanoma tumors, the scientists observed as many as 13 extra copies of the MITF gene in 10 percent of primary melanomas and 21 percent of metastatic tumors.

When they checked the treatment outcomes of the patients from whom the tumor samples were taken, researchers found poorer 5-year survival rates among patients whose metastases contained the amplified MITF gene.

Aside from its clinical potential, this finding highlights the recently discovered mechanism of tumor "addiction," whereby tumor cells grow to require a high level of production of a specific oncogene's protein for survival. Dana-Farber's David E. Fisher, another author on the Nature paper, showed previously that the MITF gene normally regulates the development of the skin's pigment-producing cells, or melanocytes. It appears the extra dosage of MITF protein spurs the melanocytes into malignant growth and maintains the tumor's survival.

The abnormal amplification of the MITF gene was associated with other genetic changes as well, including mutations in BRAF that were previously discovered in melanoma cells, and silencing of the tumor-suppressor gene p16.

"We might be able to treat these metastatic melanomas by targeting the MITF gene or protein, alone or in combination with drugs that block BRAF," says Sellers. "We know that when MITF activity is reduced, melanoma cells become more vulnerable to chemotherapy drugs." However, Sellers also notes that MITF is a transcription factor, and these have proven difficult to manipulate with drugs.

Caused mainly by sun exposure, the incidence of melanoma has been increasing rapidly over the past several decades. Although it accounts for just six percent of diagnosed skin cancer cases in the United States, it is the deadliest, causing three quarters of all skin cancer-related deaths.

In addition to Sellers and Fisher, authors on the paper include Levi Garraway (lead author), Dana-Farber and Brigham and Women's Hospital; Hans R. Widlund, Dana-Farber; Todd R. Golub and Matthew Meyerson, Dana-Farber, Brigham and Women's Hospital and the Broad Institute; Jinyan Du, Dana-Farber and Broad Institute; Sridhar Ramaswamy, Broad Institute and Massachusetts General Hospital; Gad A. Getz, Broad Institute; Mark A. Rubin, Danny A. Milner, Scott R. Granter and Charles Lee, Brigham and Women's Hospital; David L. Rimm and Aaron Berger, Yale University School of Medicine; Stephan N. Wagner, Medical University of Vienna in Austria; and Cheng Li, Dana-Farber and Harvard School of Public Health.

Adapted from a release by Dana-Farber Cancer Institute.

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