Dana-Farber's Levi Garraway, MD, PhD, and William Sellers, MD, the paper's first and senior authors, and their colleagues will report their findings in the July 7 issue of the journal Nature.
"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," explains Sellers, who also holds an appointment with the Broad Institute of Harvard and MIT and with Harvard Medical School.
Melanoma accounts for just six percent of diagnosed skin cancer cases in the United States, but it is the deadliest, causing three quarters of all skin cancer related deaths. The American Cancer Society estimates that 7,700 melanoma patients will die this year.
Caused mainly by sun exposure, melanoma has been increasing rapidly over the past several decades. Nearly 60,000 new cases are expected in 2005. Most cases caught early can be cured, but if melanoma cells penetrate the skin deeply, the cancer is highly prone to spread with life-threatening consequences despite treatment with surgery, chemotherapy and radiation.
The researchers used single nucleotide polymorphism (SNP) array technology, which focuses on the building blocks of individual genes, to identify regions of chromosomes where genes were either left out or multiplied over and over – mistakes that are 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 metasases contained the overcopied or "amplified" MITF gene.
Abnormal amplification of the MITF gene was found to be associated with other genetic changes as well. They included mutations in a gene, BRAF, previously found in melanoma cells, and silencing of p16, a "tumor-suppressor" gene that normally keeps cells from dividing too rapidly and causing cancer.
Aside from its clinical potential, the scientists say the finding advances the understanding of cancer: It highlights a previously unknown mechanism by which a tumor can become "addicted" to an oncogene that, in its normal form, plays a role in developing and maintaining tissues. That is, the tumor cannot survive without a high level of production of the oncogene's protein. Dana-Farber's David E. Fisher, MD, PhD, an author on the paper, has previously shown 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.
"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, he said, MITF is a "transcription factor" that controls the expression of other genes, and these factors have proven difficult to manipulate with drugs.
The papers other co-authors are Hans R. Widlund, PhD, Dana-Farber; Mark A. Rubin, MD, Danny A. Milner, MD, Scott R. Granter, MD, and Charles Lee, PhD, Brigham and Women's Hospital; Gad A. Getz, Broad Institute of Harvard and MIT; David L. Rimm, MD, PhD, and Aaron Berger, Yale University School of Medicine; Sridhar Ramaswamy, MD, Broad Institute of Harvard and MIT and Massachusetts General Hospital; Jinyan Du, PhD, Dana-Farber and Broad Institute of Harvard and MIT; Stephan N. Wagner, MD, Medical University of Vienna in Austria; Cheng Li, PhD, Dana-Farber and Harvard School of Public Health; Todd R. Golub, MD, and Matthew Meyerson, MD, Dana-Farber, Brigham and Women's Hospital and the Broad Institute of Harvard and MIT.
The research was supported in part by grants from the National Institutes of Health, the Swedish Wenner-Gren Foundation, the Austrian Academy of Sciences, the Howard Hughes Medical Institute, the American Cancer Society, the Flight Attendant Medical Research Institute, the Tisch Family Foundation, and the Damon Runyon Cancer Research Foundation.
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
Journal
Nature