The Story of GNAQ

Two common mutations in GNAQ occur in a majority of cases of one form of eye cancer, known as an uveal melanoma.

From twinkly blue to mossy green and deep black, the color of our eyes is one of our most distinctive features. The pigmented layer of cells that colors our eyes extends deep within, forming a thin layer called the uvea, which includes the iris and two deeper eye structures, known as the choroid and ciliary body. These deeper layers rarely encounter the light but the melanocytes, or pigment cells, in the uveal layers are much like those in our skin.

A genetic predisposition or too much time in the sun can lead to freckles on the iris, dark mole-like flecks of cells clumped together. Such growths are often harmless. But they’re also where the most common eye tumors – known as uveal melanomas – originate in adults. Nearly 80 percent of uveal melanomas carry a mutation in GNAQ or GNA11, two genes that carry the blueprint for parts of a protein that helps to convert signals from outside a cell into actions inside a cell.

Cells that carry mutated GNAQ nearly always have one of two mutations: a different letter in the gene’s sequence alters the protein, either at its 183rd amino acid or the 209th one. Either one can cause the protein to malfunction. How do such tiny errors trigger a melanoma?

The first clues that GNAQ might have something to do with the growth of pigmented cells came from mice. In 2004, scientists noticed that mutations that increased the activity of the GNAQ and GNA11 proteins could increase the formation of dark pigmented melanocytes in the skin of mice. A few years later, the link between these genes and human melanomas clicked into place. Although melanomas from different skin sites had many sorts of mutations, those that originated in the eye – the uveal melanomas – had surprisingly frequent mutations in GNAQ or GNA11.

Skin cancer often begins as a dark mole, known as a blue nevus, or nevi in the plural. In mice, a mutation of GNAQ or GNA11 almost always forms such nevi. Melanomas in the eye often start off as nevi too, which look like blue-grey freckles on the iris or other parts of the uvea. (It’s harder to biopsy a benign growth in a human eye, but it is likely that GNAQ mutations trigger such nevi.)

When pigmented cells in these nevi or moles turn cancerous, they typically acquire mutations that drive their cells to divide uncontrollably. The driving mutations commonly seen in skin cancers are only seen occasionally in eye melanomas. But a mutated GNAQ can turn on intracellular pathways in pigment cells of the eye in much the same way other genes do in skin cells. Here’s how those pathways work – it gets a little complicated, but bear with us as we explain some biochemistry:

In healthy cells, the GNAQ gene makes part of a protein called G-protein that stays perched on the cell membrane, with one end dangling into the cell and the other sticking up outside. The part that’s outside can attach to hormone molecules and nutrients, or respond to other signals, and it is GNAQ that makes this binding protein. When there are no signals from the outside, the inactive protein is bound to GDP, a tiny energy-storing molecule.

When a signal comes in, the G-protein swaps this bound GDP molecule for a related molecule known as GTP. This sets off a storm of signals inside the cell that make cells multiply. Shortly after, the G-protein transforms its GTP molecule back into a GDP molecule and turns off, silencing the intracellular pathways. GNAQ encodes the G-protein’s GTP (or GDP) binding part. When its sequence is altered, the GNAQ protein fails to release GTP. So the G-protein is always turned on – and so are the signals that push cells to grow.

Other cancer-linked genes that work in very similar ways include GNA11, BRAF, and NRAS. BRAF and NRAS are often mutated in other skin cancers. But unlike these genes, which can wreak havoc in many different tissues, GNAQ mutations are most common in tumors of the uveal layer, and particularly so in tumors of the ciliary body and choroid. Since the iris is exposed to sunlight, iris cells can also acquire UV-light triggered mutations. Mutations in GNAQ seem to arise regardless of whether cells have encountered damaging radiation.

Apart from uveal melanomas, GNAQ has only been implicated in a few other cancers, such as primary melanocytic neoplasms of the central nervous system, and one instance of mucosal melanoma. Even in the eye, simply having a GNAQ mutation does not mean a cell will turn cancerous. A few more cellular steps usually lie between a harmless cluster of colored cells and a dangerous melanoma – but for now, they’re a mystery.

What scientists know is that GNAQ or GNA11 mutations occur very early in the formation of a uveal melanoma. But these proteins have little impact on the size of a tumor, whether it can metastasize, or how it will respond to treatment. At present, there are no drugs that can turn the mutated form of GNAQ off. However, many kinds of therapy can correct the faulty cellular cascades that a mutant GNAQ triggers. These downstream effects – unlike GNAQ mutations – are surprisingly common across a breadth of cancers.

Rather than targeting GNAQ itself, therapies for metastatic uveal melanoma can be aimed at the proliferation-signaling pathways it triggers inside cells. Selumetinib and trametinib (marketed as Mekinist), drugs which target the MEK pathway (which includes GNAQ), are some therapies currently in clinical trials. Others include vorinostat, which targets a gene known to increase risk of metastasis. Preclinical studies also suggest that verteporfin (marketed as Visudyne), which inhibits the activity of YAP – another of GNAQ’s targets – may prove effective in treating metastasized melanomas.

Despite being so common, GNAQ mutations in uveal melanoma still say little about the prognosis or treatment options for this type of cancer. However, knowing the GNAQ status of a tumor may help clinicians identify the origin of a cancer. Someday, this could also lead to better ways to target cancers that carry a mutated GNAQ gene.

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