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Researchers find molecular markers flagging presence of small metastases before reaching life-threatening size

American Association For Cancer Research (AACR) : 19 June, 2007  (Technical Article)
Patients with melanoma of the eye are at risk for liver metastases, which are often not detected until they have turned into large, lethal tumors. Now researchers have found molecular markers, including changes in a particular chromosome, that flag the presence of small metastases before they reach life-threatening size.
In a second important finding, the researchers showed that a common procedure, called fine needle biopsy, could be used to accurately detect these molecular signatures.

“The results show that we can pinpoint these molecular markers in the small amount of RNA and DNA obtained from fine needle biopsy,” said principal investigator J. William Harbour, M.D., Associate Professor of Ophthalmology/Cell Biology/Medicine at Washington University School of Medicine in St. Louis.

“This means that testing for the markers is clinically feasible and could be used routinely to identify patients with ocular melanoma who are at high risk for metastasis.”

Results were presented at the first meeting on Molecular Diagnostics in Cancer Therapeutic Development, organized by the American Association for Cancer Research.

In prior studies, Dr. Harbour and his colleagues found that a particular molecular signature, the pattern of expression, or activation, of a group of 3 to 10 genes, was an accurate predictor of metastasis. On the basis of this gene expression pattern, patients with ocular melanoma can now be divided into two groups: Those with a class 1 molecular signature have little risk of metastasis while those with a class 2 signature have a high risk.

In this study, the St. Louis researchers first tested whether the minute quantities of RNA obtained from fine needle biopsies were adequate to detect the class 1 and class 2 signatures. The results were positive. The signatures obtained from the fine needle biopsies corresponded to signatures obtained through conventional biopsies and to those found in the earlier studies.

Secondly, the researchers found that DNA from the fine needle biopsies included another biomarker: On chromosome 8, the loss of DNA in the p region correlated with time to metastasis. Among patients with 8p loss, the median time to metastasis was 25.8 months while for those without 8p loss, it was 37.4 months.

The authors conclude that RNA- and DNA-based testing of fine needle aspirates is clinically feasible and accurately predicts metastatic risk and time to metastasis in ocular melanoma.

The next step, Dr. Harbour said, is a larger, multicenter study in which cancer centers around the country will obtain fine needle aspirates from ocular melanoma patients and send them to Washington University for analysis. If this study confirms the usefulness of the procedure on a large scale, it could become routine practice.

Patients at high risk for metastasis could then opt for further, preventive treatment, including clinical trials of new targeted agents and immunotherapies, Dr. Harbour said.

“Because we can now identify high risk patients, we can design clinical trials specifically for this population,” he said. “And this could lead to more rapid development of new agents to prevent or slow down metastasis in ocular melanoma.”
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