Eyeworld

EW FEATURE 74 by Maxine Lipner Senior EyeWorld Contributing Editor Gene mutation linked to uveal melanoma Genetic connection found for the most common form of eye cancer A gene associated with uveal melanoma has been uncovered. The gene, known as GNA11, was found in 40% of uveal melanomas, according to Boris C. Bastian, M.D., Ph.D., chairman, De- partment of Pathology, Memorial Sloan-Kettering Cancer Center, New York. The results of this multicenter study were published in an issue of the New England Journal of Medi- cine. Uveal melanoma is in fact the most common form of eye cancer. "There are about 1,500 new cases every year in the United States," Dr. Bastian said. While primary tumors can often be successfully treated with radiation, radiation emitting plagues, or surgical removal of the eye, unfortunately many cases ulti- mately result in metastasis. "About 50% of patients develop metastatic disease, which is typically lethal," Dr. Bastian said. "About 95% of tu- mors metastasize to the liver—once that happens the disease typically leads to death within a few months." Early research The recent research built on earlier findings. In a prior study led by Catherine D. Van Raamsdonk, Ph.D., assistant professor, University of British Columbia, Vancouver, in collaboration with Gregory S. Barsh, M.D., Ph.D., professor of pediatrics and genetics, University School of Medicine, Calif., the investigators found mutations in a related gene called GNAQ. "They did a mutagen- esis screen in mice," Dr. Bastian said. "The mice were fed a mutagen in- creasing the likelihood that they ac- quire mutations in their germ cells, which they pass off to the off- spring." The group here was particularly interested in any offspring that de- veloped dark skin. "One particular phenotype that they described that attracted my interest was darkening of the dermis," Dr. Bastian said. "That is caused by an increase of dendritic or spindled melanocytes, which I have seen many times in a condition called blue nevi in hu- mans." Dr. Bastian then approached the investigators and suggested looking more closely at blue nevi in relation to either GNAQ or GNA11. "I sent a large number of blue nevi to [Dr. Raamsdonk] and she found muta- tions in GNAQ, but not in GNA11," Dr. Bastian said. It then occurred to Dr. Bastian that there was a possible connection between blue nevi and uveal melanoma. "There is a particu- lar type of blue nevus that is called nevus of Ota, which is a segmental blue nevus," Dr. Bastian said. "There is a slate-gray pigmentation of the temporal area of the forehead, which is typically unilateral—it can also involve the sclera." In such cases, the sclera becomes grayish. While this commonly occurs in Asians and is not a risk factor for uveal melanoma, in Caucasians, however, there is a connection to the disease. "Once that light bulb went off in my head, I thought we should look at uveal melanoma because that had for the longest time been notorious for not having an onco- gene assigned," Dr. Bastian said. Uveal mutations He had a strong sense that muta- tions were going to be found there. "We did find frequent mutation in GNAQ, but at that time we had al- ready dismissed GNA11 because we didn't find any mutations in blue nevi; we thought only GNAQ played a role in humans," he said. "How- ever, at some point later we went back and sequenced more tumors for GNA11." Investigators found that the mutation was indeed very rare in blue nevi, only occurring in about 5% of cases; however, it was much more common in uveal melanoma and uveal melanoma metastasis. In the New England Journal of Medicine study investigators se- quenced over 700 melanocytic tu- mors of various types. "Actually 90% of metastatic uveal melanoma metastasis has mutations in either gene GNA11 or GNAQ," Dr. Bastian said. He finds that these are com- pletely exclusive with patients hav- ing a mutation in one or the other, but not both. "The reason is that they both do the same thing so there's no need or advantage for cells to carry both," Dr. Bastian said. Some signaling pathways have been found that get activated inap- propriately by those genes. "One of them is called a mitogen-activated protein kinase pathway (MAP ki- nase)," Dr. Bastian said. "That is acti- vated in many cancers, and there are some drugs that target this pathway at various levels." One important component is a protein called MEK. "There are specific inhibitors from several companies that have shown some successes in other cancers with activation of that pathway," Dr. Bas- tian said. A new clinical trial involving MEK inhibitors and uveal melanoma patients has been initiated at Memo- rial Sloan-Kettering by Gary K. Schwartz, M.D., chief of the Center's melanoma and sarcoma service. "We have some laboratory data in cells from patients with uveal melanoma that carry [GNA11 or GNAQ] muta- tions and found that those cells are highly susceptible to this inhibitor," Dr. Bastian said. "We hope that this is a first step to a targeted therapy approach for uveal melanoma." Investigators have found that both the GNA11 and the GNAQ mu- tation can work to inactivate the en- zyme GTPase function. As a result, the signaling pathway enzymes are turned on and can't turn themselves off. Dr. Bastian likens this to a stuck gas pedal. Based upon these recent devel- opments Dr. Bastian is hopeful that progress in combating uveal melanoma can now be made. "We now have a mechanism, we know what drives this, and we know what gas pedal is stuck," he said. "Now we have to explore the consequences of that stuck gas pedal, so to speak— the oncogenic output to look for drugable targets." In addition, more research needs to be done on how these mutations arise and on possi- ble ways to prevent the disease. Overall, Dr. Bastian is opti- mistic. "This is an important step forward in understanding the cause of this disease," he said. EW Editors' note: Dr. Bastian has no finan- cial interests related to his comments. Contact information Bastian: BastianB@maskcc.org February 2011 RETINA October 2011 Uveal melanoma Source: of David H. Abramson, M.D. 68-75 Feature 2 AMD_EW October 2011-DL2_Layout 1 9/29/11 3:48 PM Page 74

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