Uveal melanoma, though rare in general, is the most common form of eye cancer — and a highly aggressive one at that. About half of all uveal melanomas that arise metastasize, at which point they're identified as class 2 tumors. Because approximately 90 percent of class 2 tumors — for which there is no treatment and the average patient's life expectancy is less than a year — are associated with monosomy at chromosome 3, the Washington University in St. Louis School of Medicine's Anne Bowcock and her colleagues sought to sequence candidate genes specific to class 2 uveal melanomas there.
However, Bowcock says that her group and others were unable to detect what they had hypothesized was a metastasis suppressor gene using that approach. "Then we decided to do a pilot experiment [involving] two class 2 melanomas and … do whole-exome sequencing on them," she says. Upon their initial analysis, one gene stood out, "and that was BAP1, which had a nonsense mutation in one tumor," which rendered a premature stop codon, Bowcock says. "This was exciting because no other gene had that characteristic," she adds. The other class 2 tumor exome had an 11-base pair deletion in exon 11 that "put the BAP transcript out of the frame, which would lead to premature termination and predicted nonsense-mediated decay," she says.
Next, the team interrogated all BAP1 exons in 29 additional class 2 and 25 class 1 samples via Sanger re-sequencing. Overall, they found that 84 percent of the class 2 tumors they surveyed showed mutations in BAP1, which led the team suggest that the gene is the "putative metastasis suppressor" they had been searching for, she says.
In subsequent in vitro analyses, Bowcock et al. found that BAP1-knockdown cell lines showed class 2 tumor characteristics, "both in terms of rounding up and looking more stem cell-like, and in terms of the genes that they [started] to express," she says.
Bowcock says her group's findings could have clinical implications. "It may be possible, in the long term, to assay for circulating cells with BAP1 mutations" in order to predict metastasis, she says, adding that researchers must first come to fully understand the BAP1-protein's functions.