"We know now that BAP1 is the big player in class 2 tumors, but there are other players, too," Bowcock adds. "We'd also like to understand what other genes are mutated in class 1 tumors and why they don't metastasize."
Bowcock and Harbour identified a single class 1 tumor with a BAP1 mutation. One possible explanation for that finding may be that the tumor was evolving into a class 2 tumor.
In a second series of experiments, the researchers found that if they put ocular melanoma cells in culture and depleted their supply of BAP1, the cells began to change in appearance and to resemble class 2 tumors in just five days.
"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," Harbour says.
He says it remains unclear whether class 1 and class 2 tumors are different from their very inception or whether ocular melanoma tumors begin their existence as class 1 tumors and then, eventually, 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," Harbour explains. "But that is still somewhat speculative, and we'll need to do more experiments to test that hypothesis."
The BAP1 mutation represents only the second common genetic mutation ever reported in ocular melanoma, and it is the only mutation linked to metastasis in this type of cancer.
"This finding will fundamentally alter the concepts and methodologies employed in patient management and in research in this field," Bowcock says. "For example, it should lead to new diagnostic tests to distinguish benign from malignant growths of the eye, which could avoid thousands of needless, vision-threatening t
|Contact: Jim Dryden|
Washington University School of Medicine