Researchers Uncover Gene for Melanoma of the Eye Jim Breitfeller

"If ever a cancer gene were discovered in the right place and at the right time, GNAQ may be it. The gene has been known for years but not linked to cancer. Now researchers say that it is mutated in patients with uveal melanoma and may be an important cause of this rare cancer, which arises from cells that give color to the eye.

The gene is in the right place because it belongs to a pathway that is activated in melanomas of the skin and has been the subject of considerable research. Drug companies are already investigating the pathway, known as the MAP kinase pathway, to develop targeted therapies for cancers other than uveal melanoma.

The time is right because of these investigations, and also because uveal melanoma may be a candidate for emerging RNA-based therapies. For example, the cancer frequently spreads through the bloodstream to the liver, and RNA delivery works particularly well in the liver.

Melanomas of the skin and the eye are biologically distinct diseases, though some of the same pathways are overactive in each. GNAQ mutations are an alternate trigger for the MAP kinase pathway, according to results published online in Nature December 10.

"Mutations in GNAQ activate a critical signaling pathway in melanoma, but it somehow enters the pathway from a different branch than melanoma of the skin," said lead investigator Dr. Boris Bastian of the University of California, San Francisco. "This may explain why the gene has not been found to be mutated in cancer until now."

GNAQ mutations were present in half of the uveal melanoma cases surveyed, and the mutations were not found in surrounding tissues.

The findings are confirmed by a follow-up study in the December Investigative Ophthalmology & Visual Science led by Dr. William Harbour of the Washington University School of Medicine.

"These authors have uncovered a mutation that certainly makes sense as a critically important mutation for uveal melanoma," said Dr. David H. Abramson, chief of ophthalmic oncology at Memorial Sloan-Kettering Cancer Center. "And what's exciting is that the discovery has the potential to go quickly from a lab experiment to a clinical treatment. Drug companies are already looking at this pathway because of other cancers."

About 1,500 cases of uveal melanoma are diagnosed each year in the United States. Although local treatment such as surgery and radiation is somewhat effective in uveal melanoma, half of the patients develop metastases to the liver even if the primary site has been effectively dealt with and controlled.

Given that some patients have metastatic disease at the time of diagnosis, what's desperately needed is a systemic therapy, said Dr. Abramson. The discovery of GNAQ represents an important step in that direction, he added.

GNAQ had been analyzed in large-scale cancer genome projects, but it went undetected as a cancer gene because the collections of melanoma samples have not been sufficiently diverse to include this rare subgroup, Dr. Bastian noted.

The project began serendipitously at a pigment cell biology meeting in 2003. Dr. Bastian heard a talk about mice developed in the laboratory of Dr. Gregory Barsh at Stanford University. The mice had a mutation that caused pigment cells to accumulate in the deep layer of the skin and resulted in bluish-black coloring on their ears and tails.

The coloring reminded Dr. Bastian of a skin condition in humans known as blue nevus, and he wondered whether the same mutations were involved. An analysis of DNA from blue nevi revealed GNAQ mutations in 80 percent of the samples. The mutation turned up only once in skin melanoma samples, however. But because a type of blue nevus is associated with a risk of uveal melanoma, the researchers looked for GNAQ mutations in that disease, and they found them.

"It's fascinating how similar the mice and the humans were in this situation," said Dr. Catherine Van Raamsdonk of the University of British Columbia, who did the analysis. "In each case, the mutations caused pigment cells to accumulate in the deep layer of the skin."

The findings raise an interesting question: Why are GNAQ mutations relatively harmless when they occur in the skin but may cause cancer in the eye? "We don't yet know why that is," said Dr. Van Raamsdonk. Benign nevi can arise within the eye, but researchers do not know whether they also carry the mutation because the nevi are not biopsied.

In recent years Dr. Bastian and others have been making the case that melanoma is actually more than one biologically distinct disease, as has been demonstrated for many cancers. The finding of GNAQ mutations in uveal melanoma and blue nevi potentially identifies them as biologically related subtypes. Mutations have also been reported in melanomas of the mucosa, palms, soles, and nail beds, suggesting that these are biologically distinct.

A critical task for the future, said Dr. Bastian, is to classify melanomas and develop therapies targeted at the genetic features underlying each form of the disease.

His laboratory is collaborating with Alnylam Pharmaceuticals to develop a therapy for silencing GNAQ in the liver. Experiments in cellas showed that introducing a small piece of genetic material (siRNA) to silence the gene caused the cancer cells to die. Alnylam has developed siRNAs for delivery to the liver in animal models, and the goal will now be to develop a panel that could selectively silence GNAQ.

Dr. Abramson praised the new studies as examples of synergy in science that does not happen often enough. "In both cases, excellent basic scientists were collaborating with excellent clinicians in work that is basic science and that could be quickly applicable to humans," he said. "That's a credit to all of them."

Source: NCI Cancer Bulletin:December 16, 2008 • Volume 5 / Number 25

Jimmy B