Murat Günel, M.D., HS ’98, can now look at the MRI of a patient with meningioma and tell with almost complete certainty which genetic mutation is causing the tumor, based solely on the tumor’s location in the brain. Moreover, in time he may be able to cure the tumor without ever wielding a surgical blade.
Whereas most tumors contain a dizzying array of garbled DNA and broken chromosomes, making it difficult to target any single molecular abnormality for therapy, Günel’s group found that meningiomas—which arise from the membranes covering the brain and are the most common form of primary brain tumor—feature only one or sometimes two key mutations in just five genes. What’s more, these mutations are closely tied to the biology of the tumors, including their location and malignant potential, as reported in the March 1 issue of Science. These findings, said Günel, the Nixdorff-German Professor of Neurosurgery and professor of neurobiology and of genetics, can point the way to more straightforward treatment for meningiomas, which presently affect about 170,000 people in the United States.
Although 90 percent of these tumors are histologically benign, they sometimes require surgical treatment because they can invade such critical neurovascular structures as the optic canal. The 10 percent of meningiomas that are malignant also require surgical removal, as no medical therapies are currently available.
The culprits in about half of all meningiomas are mutations in the tumor suppressor gene neurofibromin 2, or NF2. Until now, however, the mutational causes of the other half of meningiomas remained a mystery.
To crack the case, Günel and his colleagues scoured meningioma exomes using whole-exome sequencing technology developed at Yale. Their search turned up four new genetic culprits. Two of the mutated genes, SMO and AKT1, have been implicated in other cancers, including basal cell carcinoma and medulloblastoma. Another gene, KLF4, maintains embryonic stem cells and can prevent their differentiation. TRAF7, the fourth gene identified, occurs in about a quarter of all meningiomas but had not been previously linked to cancer.
The scientists found that these genetic defects do not run in the same circles. Rather, they are mutually exclusive of NF2, the suppressor gene, and sometimes even of one another. In about a third of the defects, the researchers found, TRAF7 mutations worked in tandem with either KLF4 or AKT1 mutations.
Günel’s group also discovered that these distinct mutational groups can predict where the meningioma will appear and how it will affect the brain. For example, tumors with NF2 mutations border the brain’s hemispheres and feature genomic instability that can lead to malignancy. In contrast, tumors with SMO mutations arise from the skull base near the midline where surgery is difficult, but they show a stable genetic profile that suggests they will remain benign. “One of the next steps is to perform clinical trials to see if we can cure these meningiomas with targeted therapies,” said Günel.
These findings represent a breakthrough in treating meningiomas and also malignant brain cancers. Günel believes that malignant tumors are basically conglomerations of the different individual types of cells that form benign tumors. “If we have the drugs to attack all of those subpopulations, then curing a malignant tumor is not going to be different than curing a benign tumor. The problem is that we didn’t have the tools until recently to understand the complex genomic nature of these cancers and how we would attack all of the cancer at the same time.”