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Gene expression profiling may predict risk for uveal melanoma
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Discoveries about the causes and progressive behavior of uveal melanoma have led to a new way to identify the condition at less advanced stages and possibly the development of a more effective therapy, according to a researcher.
“Even though we’ve had steady improvements in diagnosing and treating uveal melanoma over the past century, there’s really been no measurable improvement in survival,” J. William Harbour, MD, said at Retina 2012. “This is a type of cancer that micro-metastasizes at a very early stage and remains dormant for years and years, and we have no effective therapies for advanced metastatic disease.”
The key to detecting uveal melanoma in its earlier stages is creating a way to identify patients who are at high risk for harboring micrometastatic disease.
“A number of years ago, we explored the possibility of gene expression profiling as a dynamic, multidimensional, highly robust approach to looking at functional differences within the tumors,” Dr. Harbour said.
In gene expression profiling, a biopsy is obtained. The biopsy can then be compared with biopsies of known uveal melanoma cases to determine whether the tumor is at high risk for metastasis.
When this process was performed in patients, the software determined that uveal melanomas cluster into two groups: class 1, which has a low metastatic rate, and class 2, which has a high metastatic rate. Class 2 patients have a higher risk for developing metastatic disease and should be monitored closely, he said.
“This is not perfect,” Dr. Harbour said. “There were a few patients that were class 1 who developed metastatic disease. But it’s by far the best that we have. It’s much better than chromosomal testing.”
After determining that class 2 uveal melanoma genes had a specific differentiating signature, exome capture and deep sequencing identified mutations in the gene encoding the BRCA1-associated protein (BAP1), located on chromosome 3p21, in metastasizing class 2 tumors but not in the less aggressive class 1 tumors. Dr. Harbour said that he was surprised to find that one of the patients with a BAP1 mutation in their tumor also had a germline BAP1 mutation.
“We don’t normally think of uveal melanoma as being a familial or hereditary cancer. We now know that the germline BAP1 mutations are the cause of a new cancer predisposition syndrome that includes uveal and cutaneous melanoma, mesothelioma, meningioma and other cancers,” he said.
Physicians should consider germline BAP1 testing in uveal melanoma patients if they are younger than 30 years old and have a personal or family history of the condition, a personal history of more than one other primary cancer, or two or more first-degree relatives with cancer not linked to smoking, he said.
Mutation of BAP1 may be the rate limiting step in the development of the class 2 signature and metastasis.
“If we knock down BAP1 in uveal melanoma cells in culture that are class 1, it shifts them toward class 2, suggesting that BAP1 may be regulating the switch from non-metastasizing class 1 to metastasizing class 2. When you lose BAP1, the equilibrium gets driven in the direction of the opposing enzyme within the PRC1 complex. If we could block the PRC1 complex, we might be able to reverse the effects of BAP1 loss,” Dr. Harbour said.
“That’s exactly what HDAC inhibitors do,” he said. “We can show in culture that we can take class 2 cells and drive them to class 1 cells. In animals, we can take tumors and prevent them from growing in vivo using HDAC inhibitors.”
Clinical trials for HDAC inhibitors in BAP1 uveal melanomas are being planned, and new classes of targeted compounds designed to offset the effect of BAP1 loss are in development, Dr. Harbour said. – by Daniel R. Morgan
Reference:
Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330(6009):1410-1413.
For more information:
- J. William Harbour, MD, can be reached at Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110; email: harbour@wustl.edu.
- Disclosure: Dr. Harbour may receive royalties based on a license of related technology by Washington University to Castle Biosciences.