The Story of GNA11

Look this gene straight in the eye and you’ll see one of the body’s on-off switches, and a key to certain cancers.

Take a look at your own eyes in the mirror.
Now imagine you could zoom in, traveling deep inside them. At the base of the iris you would find tiny cells that help give the iris its color. In each of these cells, called melanocytes, molecules are telling cells when to split in two. One such molecule is called GNA11, which is an ancient protein found in everything from sea squirts to mice and humans. GNA11 plays many roles throughout the body, but genetic changes can alter its shape, leading to cancer of the uvea, the thin layer of tissue beneath the white of the eye.

To understand how changes in the instructions for making the GNA11 protein can lead to cancer, it’s important to see how this protein interacts with the linchpin of many cellular functions, the G-protein-coupled receptor (GPCR). These giant receptors span the cell’s membrane and act as gatekeepers. They take chemical messages from outside the cell and transmit signals to the cell’s interior. About 1,000 different types of GPCRs respond to individual chemicals’ signals. Some of those signals tell muscles to fire, while others tell cells to divide. Though these receptors are found in all complex life forms and play a role in virtually every known function in the human body, many scientists didn’t even believe they existed till the 1970s.

The GNA11 protein is just one teammate in the relay race of molecules that causes the cell to divide. Normally, GNA11 sits on the inside surface of the cell and acts as a roadblock to cell division. In its usual state, one part of GNA11 tightly grips a chemical called guanine diphosphate (GDP), locking GNA11 safely in the “off” position. But when conditions are right, a chemical outside the cell binds to the G-protein-coupled receptor or GPCR described in the above paragraph. This, in turn, forces the receptor to change its shape inside the cell and GNA11 then nestles perfectly inside the changed receptor.

In doing so, GNA11 releases its grasp on GDP, the chemical that ordinarily keeps it locked safely on the “off” position and swaps it for a modified form of the molecule called guanine triphosphate (GTP). At this point, a switch has been flipped. GNA11 unfurls and is officially “on.” It can now modify another molecule, called protein kinase C, which sets off a chemical cascade, known as the mitogen activated protein kinase (MAPK) pathway, that tells the cell to divide. This is the GNA11 protein in its normal condition, able to be turned on, or off, initiating cell division, or not, according to the body’s needs.

Sometimes, however, the nucleotides, or letters in the gene that makes the protein GNA11, get changed. These mutations essentially tweak the binding portion of the GNA11 protein, jamming GNA11 into a permanent “on” state. For that reason, a mutation in the GNA11 gene can allow the pigment cells in the eye to divide indiscriminately. Mutations that keep GNA11 on all the time show up in about one-third of cancers of the uvea, which includes the iris and surrounding parts of the eye called the choroid and ciliary body.

But GNA11 isn’t the only protein tied to uveal melanoma; it has a lookalike, called GNAQ, which also plays a similar role. Scientists suspect that on their own, mutations either of these two G-proteins wouldn’t cause cancer. Instead, these mutations seem to act in concert with other genetic changes, such as changes to a gene called RASSF1A that encourages cells to grow old, which then allows cells to divide indefinitely.

It’s not clear exactly how mutations in these G-proteins arise. We do know that older people, those with light skin or eyes, and those who tan easily have a higher risk of developing uveal melanoma or ocular cancer. In contrast to skin cancer, scientists haven’t found a clear link between ocular melanoma and ultraviolet light exposure.

What doctors look for – to see if the GNA11 or GNAQ gene has changed – is a stretch of bluish grey pigmentation in the eye, called the Nevus of Ota. Though not cancer itself, the Nevus of Ota can be a warning sign that mutations in these two genes have made cancer more likely. Other warning signs for uveal melanoma include blurred vision, flashing lights, and floaters. Many people with eye cancer have no symptoms and are diagnosed at a routine eye exam.

About 50 percent of uveal melanomas will metastasize, or spread, within 15 years. Almost all of these metastases are to the liver. But it matters greatly where the cancer originates. For instance, cancers of the iris spread only 2 percent of the time, whereas cancers of the choroid have a roughly 30 percent chance of spreading within five years.

When cancer has not spread, there are many options to treat the condition. In some cases, doctors will monitor a small tumor to make sure it doesn’t grow. In other cases, doctors cut out the tumor. Whether doctors remove just a sliver of the eye or the entire eye, eye socket and surrounding muscles depends on how large the tumor is and how much it has changed pressure inside the eye. Other patients may receive radiation therapy or heat treatments to kill the cancer cells.

For those whose cancer has spread, however, there are no approved medicines or treatments. This is where GNA11 comes in. Researchers have found mutations in the GNA11 gene in more than half of metastatic uveal cancer cells they have tested. In theory at least, preventing GNA11 from being activated could help treat metastatic uveal melanoma.

Doctors haven’t yet developed treatments that target GNA11, in part because uveal melanoma is so rare. But targeting GNA11 is not the only possible way to fight metastatic uveal melanoma. One approach is to retrain people’s immune systems to attack cancer cells. In one clinical trial, doctors are testing the
safety and dosage of a drug called ipilimumab (marketed as Yervoy), which has worked for other forms of melanoma. Ipilimumab helps unleash the power of T lymphocytes, blood cells that normally kill foreign and abnormal cells.

In addition, GNA11 is just one player in cell division – and not even the star player. If doctors could put the brakes on some other part of the cell division process, metastatic cancer could be slowed or even halted. As mentioned earlier, GNA11 is a part of the major MAPK cell division cascade, the pinball-like interaction of chemicals that gives instructions to the cell to divide . Problems in the control of these pathways lie behind many cancers, from melanoma to ovarian cancers.

As a result, some scientists have wondered whether medicines that halt cell division at other points in the MAPK pathway could also fight cancers with GNA11 mutations. This research is still in early phases. For instance, blocking the action of protein kinase C, along with other molecules in the MAPK pathway, seems to slow the growth of uveal metastatic cancer cells in a petri dish. Further along in development, a clinical trial in people is testing the safety and effectiveness of two drugs in concert: an experimental drug called AEB071 that blocks the formation of protein kinase C and another called MEK162 that targets molecules further down the cell division signaling chain.

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