Catherine Van Raamsdonk, an assistant professor of medical genetics in the UBC Faculty of Medicine and a team of researchers, have discovered a genetic mutation in a gene called GNAQ that could be responsible for 45 per cent of the cases of uveal melanoma.
The findings, published today in Nature , will allow researchers to develop therapeutic interventions against some melanomas.
"We discovered that GNAQ regulates melanocyte survival," says Van Raamsdonk. "When the GNAQ gene is mutated it leads to unregulated growth of melanocytes. Since cancer is a disease of unregulated cell growth, our findings led us to the discovery that a genetic mutation of the GNAQ gene causes uveal melanoma."
Uveal melanoma is a cancer arising from melanocytes located in the uveal tract. The uveal tract is one of the three layers that make up the wall of the eye. A melanoma is unregulated growth of melanocytes. Melanocytes are also found in the skin and are cells linked to a life-threatening form of skin cancer.
The mutation to GNAQ leads to the activation of a signaling pathway that has previously been implicated in many other types of melanoma. The researchers also found that this mutation is a key factor in the development of a type of benign skin mole - blue naevi.
"Prior to our work, the mutations responsible for uveal melanoma were completely unknown," says Van Raamsdonk. "No other research looked at mutations in GNAQ. The next step is to develop an effective treatment by targeting the specific biological processes that this mutated gene controls."
Uveal melanoma, the most common eye cancer, affects one in 13,000 people. It is a highly aggressive cancer without any effective treatment options once it metastasizes. Although it only accounts for approximately five per cent of all melanomas, it represents the most common eye cancer in the United States.
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He then inserted a DNA tag into the mouse genome that allowed him to induce a break at the c-myc gene, which occurs only very rarely if left to its own devices. He found that his artificially created breaks were comparable in most every way to the breaks caused by AID, but when he looked for the translocation in mice that didn't produce this enzyme, they were nowhere to be found.
"This is a definitive study," says Nussenzweig, who is also a Howard Hughes Medical Institute investigator. "We now know AID is causing damage in other parts of the genome, not just in antibody genes."
Because AID normally enables the genetic experimentation that's critical to an effective immune response, shutting it down even to fight cancer is perilous. "As a general rule, you wouldn't want to give an AID inhibitor to everyone because immune systems would not be working so well," Nussenzweig says. Still, a pharmaceutical AID inhibitor, if developed, might prove useful in treating certain tumors that are expressions of this powerful gene mutator.
The next step is to figure out exactly how AID works and identify other genetic sites where AID is active. "We are now developing the tools to do exactly that," Robbiani says.
Cell online: December 12, 2008
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