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Washington University researchers have identified a gene linked to the spread of eye melanoma. Reporting in the journal Science Express, the team found mutations in the BAP1 gene in 84 percent of the metastatic eye tumors they studied. By contrast, the mutation was rare in tumors that did not metastasize. BAP1 is short for BRCA1- associated protein 1, and BRCA1 is linked to breast cancer in some women.   

Ocular melanoma, also called uveal melanoma, is the most common eye cancer and the second-most common form of melanoma, striking about 2,000 adults in the United States each year. It can affect people at any age but is most common in patients over 50. Up to half of those with the cancer eventually develop metastatic disease, which is universally fatal.   

To improve survival, scientists need to understand more about what causes the tumor cells to metastasize, according to J. William Harbour, MD, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences, director of ocular oncology at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. 

Harbour and co-investigator Anne Bowcock, PhD, professor of genetics, of pediatrics and of medicine, have been looking at DNA in tumor cells for clues about why some tumors spread. Previously, scientists had grouped tumors into two classes based on gene expression profiles. Class 1 tumors have a low risk of spreading, while class 2 tumors carry a high risk of metastasis. In addition, 90 percent of class 2 tumors have lost a copy of chromosome 3, unlike class 1 tumors, which tend to retain both copies of the chromosome. 

“We eliminated common genetic variations and then went back to look at which gene on chromosome 3 had additional alterations,” Bowcock says. “There was one gene, BAP1, that had mutations in both of the initial class 2 tumors we analyzed. We then went back and looked at DNA from another 29 class 2 tumors, as well as 25 class 1 tumors. We found that 84 percent of the class 2 tumors had damaging mutations in BAP1. We also found that in most cases, the class 2 tumor cells had only one copy of chromosome 3.” 

It appears that what the gene is supposed to do, Harbour says, is to act as a metastasis suppressor. When it is damaged, the tumor can spread. 

“There are several ways this discovery could improve patient care,” Harbour says. “If we could detect BAP1 mutations at an earlier stage, for example, we might be able to monitor a patient’s blood for detectable melanoma cells as an early sign that they’re developing metastatic disease.” 

He also says a better understanding of the normal role of the BAP1 protein could provide powerful insights into ways to therapeutically target eye tumors that are likely to spread. He and Bowcock already are beginning those studies. 

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.
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