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Scientists discover how two gene mutations cause melanoma of the eye

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Researchers have discovered how two genetic mutations can cause the development of melanoma of the eye – the most common form of eye cancer.

With a better understanding of how these genes work, the researchers say they now have a promising therapeutic target for treating the disease in the future.  In fact, the researchers were even able to slow the progression of eye tumor growth in mice by using an FDA-approved drug associated with these two genetic pathways.

“Before our study, it was well known that those two genes cause cancer,” study author Kun-Liang Guan, professor of pharmacology at UC San Diego Moores Cancer Center, told FoxNews.com.  “But the mechanisms [were] not clear.  So if we know how they do cause cancer, then we may find a way to target those mechanisms.”

Melanoma of the eye – or uveal melanoma – occurs when cancer develops in the parts of the eyes that contain pigment, most notably the iris.  If the cancer is contained to just the eye, the standard treatment includes radiation and removal of the eye, which is usually successful.  However, uveal melanoma often metastasizes and spreads to the liver, and once this occurs, patients typically succumb to the disease within two to eight months after diagnosis.

Two genetic mutations – GNAQ and GNA11 – have long been implicated in the development of uveal melanoma, occurring in up to 80 percent of all cases of this form of cancer. Both of these genes code for what are known as G proteins, which act like molecular switches, regulating the transportation of information from the outside of cells to their cells.

Upon further analysis of these genes, Guan and his team revealed that genetic mutations in both GNAQ and GNA11 cause the G proteins to be permanently “on,” letting all forms of signals to pass freely in and out of cells.  This leads to the over-activation of the Yes-associated protein (YAP), a potent oncogene that has the potential to cause cancers.

“What we know is when [these genes] are mutated, they’ll convert normal cells into cancer cells,” Guan said.  “If you overexpress the [YAP] protein in normal cells, the normal cell will acquire properties similar to a cancer cell – meaning it proliferates too much and will not die.”

Now knowing the crucial role that YAP plays in the development of cancer, Guan said that experts could potentially use the protein as a drug target to slow the spread of uveal melanoma.  Additionally, an existing drug called verteporfin, which is used to treat abnormal blood vessels in the eye, is already known to inhibit YAP’s function.

The researchers decided to test the effects of verteporfin on mice afflicted with uveal melanoma tumors derived from human tumors.  As expected, the drug helped to suppress tumor spread and saved the lives of the mice.

Given their success, Guan hopes that pharmaceutical companies will commit to developing more YAP inhibitors, since it is a fairly easy protein to target.  According to the National Cancer Institute, uveal melanoma affects 2,000 people in the United States each year.

“I think the beauty of this is the simplicity of the study,” Guan said. “We hope our study will really help develop therapies for the treatment of uveal melanomas.”

The research was published online in the journal Cancer Cell.