A gene linked to the spread of eye melanoma has been identified by researchers.
Although more research is needed, researchers at Washington University School of Medicine in St. Louis say the discovery is an important step in understanding why some tumors spread (metastasize) and others don't. They believe the findings could lead to more effective treatments.
The team found mutations in a gene called BAP1 in 84 percent of the metastatic eye tumors they studied. In contrast, the mutation was rare in tumors that did not metastasize.
Metastasis is the most common cause of death in cancer patients, yet little is known about how cancer cells evolve the ability to spread to other parts of the body. There is growing evidence that mutations in so-called metastasis suppressor genes may promote the spread of cancer, while having little to do with earlier stages in the life of a tumor. Very few such genes have been identified, but this finding strongly implicates BAP1 as a new member of that small group.
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. The tumors arise from pigment cells, called melanocytes, that reside in the layer below the retina called the uveal tract. Up to half of those with the cancer eventually develop metastatic disease, which is universally fatal.
In this study, the team looked for differences in genes on chromosome 3 between the cells in class 1 and class 2 tumors. They started with tissue taken from a pair of class 2 tumors.
"We looked for common genetic differences, called polymorphisms, that would unlikely have much of an effect," Bowcock says.
"We eliminated those variations and then went back to look at which gene on chromosome 3 had additional alterations. There was one gene, called BAP1, that had mutations in both of the tumors we analyzed."
BAP1 is short for BRCA1-associated protein 1. As it happens, BRCA1 is linked to breast cancer in some women. "It points, possibly, to a common theme in cancer genetics," Bowcock says.
"After identifying mutations in BAP1 in the first two tumors, we went back and looked at DNA from another 29 class 2 tumors, as well as 25 class 1 tumors. And 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 - 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."
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.
The report has been published online in the journal Science Express.