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1.13.2013

Bascom Palmer Researcher Identifies New Genetic Mutation in Ocular Melanoma

Bascom Palmer Eye Institute ophthalmologist J. William Harbour, M.D., has identified a new genetic marker for determining the virulence of ocular melanomas in a groundbreaking study published online January 13 in the prestigious journal Nature Genetics.

“Our research team discovered that the RNA splicing factor SF3B1 is mutated at a very specific location in some ocular melanomas, and this mutation indicates the likelihood that an ocular melanoma will metastasize and spread to other parts of the body, a far more deadly condition than when the cancer cells remain localized in the eye,” said Harbour, professor of ophthalmology, Vice Chairman for Translational Research at Bascom Palmer, and Director of the Ocular Oncology Service.

Harbour has been studying ocular melanomas for more than a decade, and in 2004 developed a genetic profiling test that indicates whether a patient has less aggressive “Class 1”cancer cells or highly aggressive “Class 2” cancer cells that often result in fatal metastasis. About 2,000 people a year in the U.S., or about 5 percent of melanoma patients, have ocular melanoma.

His new study, “Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma,” continues Harbour’s pioneering research by identifying an RNA splicing factor involved in the mutation process. Uveal melanoma, often called ocular melanoma, is an eye cancer involving the iris, ciliary body or choroid layers of the eye.

“This new study allows ophthalmologists to more fully understand the mutation landscape in ocular melanoma,” Harbour said. “Eye cancer patients can now obtain such important genetic information to allow individualized, state-of-the-art patient care.”

Using sophisticated gene sequencing technology, Harbour and colleagues found that SF3B1 was often mutated, or damaged, in ocular melanomas. Surprisingly, ocular melanomas containing these mutations were found to be associated with a better prognosis than those without the mutation. “After five years, only 20 percent of patients with an SF3B1-mutant tumor developed a metastasis, compared with 85 percent of patients without the SF3B1 mutation,” Harbour said.

The study also noted that five ocular melanoma samples from distant metastases were available for testing, and none harbored SF3B1 mutations, further supporting the notion that these mutations might be associated with less aggressive tumors.

Harbour added that the SF3B1 mutation always occurs at the same place in the gene, making laboratory testing much easier than analyzing a patient’s entire gene sequence.

“Ten years ago, virtually nothing was known about the genetics of ocular melanoma,” he said. “Now we know four of the major drivers of the disease: GNAQ, GNA11, BAP1 and SF3B1.”

Harbour began his research at Washington University School of Medicine in St. Louis, where he was the Paul A. Cibis Distinguished Professor of Ophthalmology & Visual Sciences. He found that the GNAQ or GNA11 mutations occur in about 85 percent of primary uveal melanomas.

“These mutations are found in uveal melanomas of all stages, and they are not associated with a patient’s prognosis,” Harbour said. In a groundbreaking 2010 report in the journal Science, Harbour’s team announced the discovery of BAP1 mutations in ocular melanoma that were strongly associated with metastasis and poor prognosis.

Referring to the new study, Harbour added that GNAQ or GNA11 mutations arise earlier than SF3B1 and BAP1 mutations. Interestingly, SF3B1 and BAP1 mutations were almost mutually exclusive, suggesting that they may represent alternative pathways in tumor progression, he said.

“As we learn more about the genetics of cancer, we can individualize patient care more and more,” he said. “When we know a tumor has a high risk of metastasizing, we are more interventional in our approach, such as enrolling that patient in clinical trials with new agents. In contrast, if there is a low risk, then we can treat the eye cancer without giving the patient systemic therapy.”

Harbour’s study co-authors were Elisha D. O. Roberson, Hima Anbunathan, Michael D. Onken, Lori A. Worley and Anne M. Bowcock, all of the Washington University School of Medicine.

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