Understanding the enemy — so you can fight the enemy

New Haven -- A Yale neurosurgeon has discovered four genes that cause the most common form of brain tumors, opening the door to someday treating these tumors with targeted drugs rather than surgery.

Dr. Murat Gunel, 45, led a research team that used genomic computer analysis to discover gene mutations that cause these typically benign tumors called meningiomas.

These tumors currently affect about 170,000 people in the United States. They are typically small but can grow and cause neurological problems, constricting vision, hearing and blood flow in the carotid artery. Ninety percent are benign, but some turn cancerous.

The team used genomic sequencing to make the discovery. They took a sample of the abnormal cells in the tumor and a sample of healthy cells from a blood sample. Then they ran a separate genetic sequencing program for both the tumor and the blood sample and then compared the two to look for mutations unique to the tumor.

gene mutations

Tumors with TRAF7 mutations, found in the skull base, are unlikely to become cancerous. In contrast, NF2 mutant tumors that flank the brain’s hemispheres are more likely to become malignant, especially in males. (MRI images provided by Dr. Murat Gunel and Victoria Clark at Yale)

They were surprised to discover four new genes, opening the door to learning the mechanisms for how these cause tumors and ways to treat them with already FDA-approved drugs.

"Our aim here is to use these genetic tools initially to identify these targets and then move on to individualized treatments, which is not a dream any more," said Gunel, who is also a geneticist.

Andrew T. Parsa, a professor and vice chairman of neurological surgery at the University of California in San Francisco, called the breakthrough "a landmark discovery."

"Understanding how these tumors grow molecular mechanisms is critically important to optimizing care for the patient," Parsa said. "Now we will be able to do more in-depth analysis of tumors, and we will be able to segregate those tumors that are less likely to grow back from to those less likely to grow back. That would be very helpful for patients."

The four genes, together with the previous discovery of a fifth genetic mutation called NF2, explain 80 percent of genetic makeup of these tumors.

One of the newly discovered genes, called SMO, has been implicated in a form of skin cancer called basal cell carcinoma and in a childhood brain tumor. Since the FDA has already approved a drug for fighting basal cell carcinoma, this drug potentially could be used in the future to treat these SMO brain tumors.

Another gene, called KLF4, is important in making cells more stem cell-like and potentially more cancer like, he said.

During the study, Gunel and his team also discovered that they could determine the mutation profile of the tumor based on its location in the brain. For example, SMO mutant tumors are almost always located in the frontal skull base behind the nose while the others are found in the midline of the skull base.

The location gives scientists another useful clue in diagnosing and potentially treating these tumors with chemotherapy, particularly since some tumors are difficult to approach surgically.

Gunel, who went to medical school in Istanbul and came to Yale in 1990, hopes clinical trails will begin soon, a particular help for patients at high risk for surgery or recurring disease.

"This has given us great clues in fighting brain tumors," Gunel said. "If you understand the enemy, you can fight the enemy. This is the initial step of understanding."

Victoria Clark, 26, a Yale graduate student who did most of the work on the study, said their approach to research differs from the traditional route of making a hypothesis and then testing it. Instead, the team looks at all the genes at the same time through the sequencing process.

"We don't have to guess which is more or less likely to be causing the tumor. We let the hypothesis come to us. We just do the readout," Clark said.

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