Melanoma Gene Predicts Disease Severity

Scientists find mutation in advanced cases

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HealthDay Reporter

WEDNESDAY, July 6, 2005 (HealthDay News) -- Scientists have identified a genetic mutation in some cases of advanced melanoma that indicates a worse-than-usual chance of survival.

The good news is that this particular mutation might one day provide a useful target for new drugs, although that is a big "if."

"Whether it can be targeted is a big question," said Dr. Vijay Trisal, an assistant professor of surgical oncology at City of Hope Cancer Center in Duarte, Calif., who was not involved in the research.

Trisal added, "They were very well-performed experiments that have been taken to their logical conclusions. Even though it was a small number of patients that may benefit, I think this is the line we need to pursue, and at least we are going in the right direction."

Melanoma, a type of skin cancer, is a particularly virulent form of the disease. While very early cases can be treated with simple surgery, once a melanoma has spread, the chances of recovery are slim.

The gene mutation was found to be present in about 20 percent of melanomas and is responsible for producing melanocytes, or the skin's pigment-producing cells.

The particular alteration involved too many copies of the MITF gene -- in some cases as many as 13 extra copies.

"The tumor seems to require [extra copies of] this particular gene," said Dr. William R. Sellers, senior author of the paper and an associate professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School.

This study, which appears in the July 7 issue of the journal Nature, also marked one of the first applications of a new technology, single nucleotide polymorphism array technology, which can actually see the number of copies of a genes.

"This is an unparalleled revolution," Sellers said. "We were amazed at how easy it was."

Sellers plans to apply the technology more broadly to more cancers to identify the genetic bases for how this disease develops.

According to data presented at the recent meeting of the American Society of Clinical Oncologists, the survival prospects for advanced melanoma patients has not improved over the past three decades. Only 35 percent to 50 percent of people with stage III melanoma and 5 percent to 10 percent of those with stage IV disease will achieve long-term survival, those researchers said.

The incidence of melanoma is also on the rise. The American Academy of Dermatology reports that one in 62 Americans now has a lifetime risk, a 2,000 percent increase from 1930.

"Metastatic melanoma is not a good thing," said Sellers. "Melanoma tend to be resistant to standard chemotherapy."

He hopes that the MITF gene might also be a target for novel therapies, although that achievement may be more elusive.

Preliminary experiments showed that if molecular therapies were first used to downregulate the gene, the cancer became more responsive to chemotherapy.

But drug companies tend to shy away from this type of gene, called a transcription factor, Sellers said.

Unlike kinase genes or enzymes, which have "deep pockets" that drugs can fit into, transcription factors have no obvious pockets that drugs can settle into, he explained, which makes it more difficult for a drug to work successfully, and thus more risky for a company to undertake.

More information

The American Academy of Dermatology has more on melanoma.

SOURCES: William R. Sellers, M.D., associate professor of medicine, Dana-Farber Cancer Institute, Harvard Medical School, and associate member, the Broad Institute, Boston, Mass.; Vijay Trisal, M.D., assistant professor of surgical oncology, City of Hope Cancer Center, Duarte, Calif.; July 7, 2005, Nature

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