Study Details Genetic Divergence Between Astrocytomas and Oligodendrogliomas

Treatment-resistant brain cancers develop different mutations as they become more aggressive, according to new research from Yale School of Medicine.

Gliomas are a type of brain cancer that tends to recur in patients after they receive treatment. New tumors are often more aggressive than their predecessors, and most people with this type of brain cancer eventually succumb to the disease.

Past research suggests that this happens because residual cancer cells survive and reproduce by adapting to the treatment. New research now shows that while treatment resistance is universal, the mutations that underlie it are not. In a study published Oct. 14 in Nature, Yale researchers revealed that two types of gliomas-astrocytomas and oligodendrogliomas-develop radically different mutations as they become more treatment resistant.

The findings suggest that future glioma treatments may need to be type-specific, rather than generic, says Roel Verhaak, PhD, Harvey and Kate Cushing Professor of Neurosurgery at Yale School of Medicine and senior author of the study. Because while brain cancer cells may act the same, different types of gliomas "respond quite differently to treatment on the genetic level," he says.

Glioma Mutations Point to Different Treatment Strategies

Brain cancer is relatively rare. Only around 1% of all newly diagnosed cancers in the United States occur in the brain or spinal cord. But despite being uncommon, brain cancers are a huge health burden-having the highest years of life lost of any cancer type in the country.

Part of the problem is how hard brain cancers are to treat. Gliomas, which make up around 33% of all brain cancers, are typically treated with a combination of surgery, chemotherapy, and radiation. However, particularly virulent cancer cells often survive treatment and reproduce, making gliomas "invariably deadly to patients," says Verhaak, member of Yale Cancer Center.

The biology behind this transformation is still poorly understood. Verhaak led a previous study showing that recurrent gliomas use a similar cellular strategy to develop resistance. To learn more about the mutations behind this resistance, Verhaak and his colleagues collected DNA samples from two types of gliomas in around 180 people hailing from 10 countries. All patients had two sets of samples, one collected at the time they were diagnosed, and the second from when their cancer returned.

By comparing the DNA between the two samples, the researchers could see which mutations the cancer developed between treatments. The findings confirmed that the returning gliomas were more heavily mutated than their predecessors, but what that looked like varied by glioma type.

Specifically, astrocytomas-a glioma variant that forms from a common non-neural cell called astrocytes-developed an unusual number of DNA copy mutations, meaning that they either deleted or over-replicated entire sections of the genome. Meanwhile, oligodendrogliomas, which form from the cells that insulate neurons, developed many single-point mutations in cancer genes.

Along with the last study, this new research shows that "the way that tumors respond to treatment is different if you look at the DNA, and yet so similar if you look at the phenotype," says Verhaak. This suggests that different glioma types could respond better to different treatments. For instance, ribociclib-a medication used to treat hormone-receptor positive breast cancer-could be a starting point for treating astrocytomas, as the medication targets unusual copy mutations.

Any new treatments, however, will have to contend with the existing issues facing brain cancer treatment-including how to get past the blood-brain barrier and prevent damage to existing brain cells, warns Verhaak. But these findings could contribute to better treatments for brain cancer patients in the long run.

We found what the typical changes are that occur in response to treatment. Now, the next step is, can we predict them?"

Roel Verhaak, PhD, Harvey and Kate Cushing Professor of Neurosurgery, Yale School of Medicine