U.S. scientists have identified a new metastasis suppressor gene that appears to play a role in the metastasis of ocular (uveal) melanoma and could represent a new therapeutic target. The team, from Washington University School of Medicine in St. Louis, identified mutations in the BAP1 (BRCA1-associated protein 1) gene in 84% of ocular melanoma tumors at high risk of metastasis (class 2 tumors). Mutations in the gene were only rarely identified in nonmetastasizing tumors. In subsequent studies with cultured ocular melanoma cells, they found that depleting supplies of the BAP1 protein resulted in the cells changing appearance and starting to resemble high-risk class 2 tumors within just five days.
Washington University ophthalmologist J. William Harbour, M.D., and colleagues claim the mutated gene is only the second common genetic variation to be identified in ocular melanoma. They hope the findings will help provide new insights into cancer metastasis and potentially lead to new prognostic assays and therapeutic approaches. Their studies are published online in Science Express, in a paper titled “Frequent mutation of BAP1 in metastasizing uveal melanoma.”
Ocular melanoma is the second most common form of melanoma, and affects about 2,000 adults in the U.S. ever year, Dr. Harbour and colleagues explain. In cases where the cancer does metastasize it spreads to the liver in 90% of cases, and generally leads to death within months.
Ocular melanoma is categorized as class 1 or class 2, according to gene-expression profiles. Class 1 tumors are unlikely to metastasize, while class 2 tumors have a high risk of metastasis. Unlike class 1 ocular tumors, about 90% of class 2 tumors have also lost a copy of chromosome 3.
Dr. Harbour and colleague Anne M. Bowcock, Ph.D., professor of genetics, initially looked for potentially significant mutations in chromosome 3 genes from two class 2 ocular melanoma tumors. Having already eliminated polymorphisms that were unlikely to be relevant, they identified mutations in BAP1 in both the tumors studied. They then analyzed the DNA from another 29 class 2 tumors and 25 class 1 tumors.
“We found that 84% of the class 2 tumors had damaging mutations in BAP1,” professor Bowcock confirms. “We also found that in most cases, the class 2 tumor cells had only one copy of chromosome 3, where the gene is located, so patients had only a single copy of the BAP1 gene, and because of damaging mutations, it could not fulfill its proper role in the cell.”
One of the class 1 tumors also displayed mutations in BAP1, and the researchers suggest this tumor may have, in fact, been evolving into a class 2. Having already observed that short-term depletion of BAP1 in cultured ocular tumor cells rapidly leads to a change in cell appearance, the Washington University team want to see the effects of BAP1 depletion over longer periods. “Now we’re trying to knock down BAP1 levels for weeks to months and find out whether we start to see some of the chromosomal changes that are present in class 2 tumors,” Dr. Harbour explains.
The authors admit they have yet to determine if class 1 and class 2 tumors start out with metastasis-determining mutations, or whether all ocular melanoma tumors begin as class 1 and subsequently develop cells with BAP1 mutations. “We have hints, both from experimental work and from patient samples, that the latter scenario is more likely, that the tumors start off as class 1 and evolve into class 2 tumors,” Dr. Harbour suggests. “But that is still somewhat speculative, and we’ll need to do more experiments to test that hypothesis.”
Nevertheless, professor Bowcock adds, the latest findings will open up a new avenue of research that could lead to more effective therapies. “This finding will fundamentally alter the concepts and methodologies employed in patient management and in research in this field,” she maintains. “For example, it should lead to new diagnostic tests to distinguish benign from malignant growths of the eye ... in addition, the insights gained from this research into how BAP1 functions at the molecular level might pave the way for innovative new therapeutic approaches to the previously recalcitrant problem of metastatic disease.”