Study links genetic mutations to development of uveal melanoma

Research focuses on disabling chemical triggers that are responsible for spurring malignancy in mutated cells.

Boris C. Bastian

Researchers have pinpointed genetic mutations that play a major role in the pathogenesis of uveal melanoma, the most common type of intraocular cancer worldwide, a study found.

There are no known treatments for metastatic uveal melanoma. Development of therapeutic agents hinges on identifying and disabling molecular “triggers” that are caused by mutations and result in malignancy.

“Until very recently, it was really not known what the genetic drivers of this disease were,” Boris C. Bastian, MD, PhD, the lead author, told Ocular Surgery News in a telephone interview. “The very encouraging finding is that we have identified a target.”

The study results suggested that a majority of uveal melanomas and blue nevi, a type of skin lesion, involve mutations in the oncogenes GNAQ or GNA11.

Uveal melanoma, which frequently metastasizes in the liver, originates from melanocytes in the choroid plexus, ciliary body and iris. Uveal melanoma is the only cancer type in which GNAQ and GNA11 mutations have been identified as of today, but mutations may be present in other tumor types, Dr. Bastian said.

The study was published in the New England Journal of Medicine.

Identifying signaling pathways

Dr. Bastian and colleagues aimed to identify signaling pathways containing the switches that spur the development of uveal melanoma.

“The approach that we are taking right now is to try to dissect the signaling pathways downstream and find effectors downstream of those mutations that can be drugged more readily,” Dr. Bastian said. “This will take some time. Unfortunately, because uveal melanoma is relatively rare, this isn’t a considerable market for pharma.”

An ongoing clinical trial is focused on MEK, a protein that acts as a “switch” along the signaling cascade, downstream from the GNAQ and GNA11 mutations.

However, investigators hope to find biochemical switches that are closer to the GNAQ and GNA11 mutations than MEK, which is acting further downstream in the pathway.

GNAQ and GNA11 encode G alpha proteins, which serve as molecular switches downstream from G protein-coupled receptors. The G proteins are active when bound to guanosine triphosphate (GTP) and shut off when GTP is hydrolyzed to guanosine diphosphate. The mutations in GNAQ and GNA11 disable the enzymatic activity of the G proteins.

“These are, in fact, broken enzymes that are locked in that GTP-bound state,” Dr. Bastian said. “In order to turn them off, one would have to reconstitute the enzymatic activity, which is a much tougher task than inhibiting an activated kinase such as that of BRAF.”

Sampling, sequencing

Investigators extracted DNA from tumor samples from patients with uveal melanoma and performed genetic sequencing to identify the mutations. To validate the role of GNAQ and GNA11 in forming melanomas, they injected melanocytes transformed with the mutant genes into mice to confirm tumor formation.

Results showed that between 63.2% and 74.5% of blue nevi and 83% of primary uveal melanomas had oncogenetic mutations in GNAQ or GNA11. The mutation frequency in uveal melanoma metastases was 90%.

“Finding that either one of those two genes, GNAQ or GNA11, is mutated in 83% of primary uveal melanomas and 90% of metastatic uveal melanomas is quite a significant breakthrough, basically pointing the finger at a very specific signaling pathway that seems to be of unique importance in a subset of melanocytic neoplasia,” Dr. Bastian said. “We think that this can all be explained, this unique distribution of those mutations in GNA11 and GNAQ, by the fact that this is a particular type of melanocyte that is particularly dependent on activation of those signaling pathways.”

The signaling pathways frequently altered in uveal melanoma are also altered in a range of melanocytic neoplasms. For example, mutations at the amino acid position 209 (Q209) in GNA11 were identified in 7% of blue nevi, 32% of primary uveal melanomas and 57% of metastatic uveal melanomas. Mutations affecting Q209 in GNAQ were found in 55% of blue nevi, 45% of uveal melanomas and 22% of metastatic uveal melanomas.

“The finding that mutations are also present in benign lesions such as blue nevi indicates that additional genes have to get mutated in order to allow those cells that have acquired GNAQ or GNA11 mutations to become fully transformed,” Dr. Bastian said. – by Matt Hasson

Reference:

• Van Raamsdonk, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363(23):2191-2199.

• Boris C. Bastian, MD, PhD, can be reached at Department of Pathology and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Comprehensive Cancer Center, 1275 York Ave., New York, NY 10065; email: bastianb@mskcc.org.
• Disclosure: No products or companies are mentioned that would require financial disclosure.