Gliomas are the most common brain tumors, and many start off growing slowly as “low-grade” tumors before inevitably becoming aggressive, lethal, and “high grade.” New research offers an explanation for this deadly transformation. 

In a study published in Nature Cancer, researchers at the Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute, and Massachusetts General Hospital investigated the evolution of these tumors, many of which are known to be initiated by mutations in an enzyme known as IDH. The team found that over time, these initially slow-growing tumors acquire new, cancer-driving mutations that send them into overdrive. The scientists also observed that the composition of cells in the tumor changes, further shifting the gliomas into a fast-growth mode.

Their results underscore the importance of early detection and treatment, such as with vorasidenib, which targets IDH and was recently approved by the FDA for low-grade gliomas. The study also points to possible new strategies for extending patients’ lives, including immunotherapy.  

“We did this study because we wanted to know: How do IDH mutations lead to a fast-growing tumor? Why do they ultimately kill the patient?” said study senior author Brad Bernstein, an institute member at Broad and director of the Gene Regulation Observatory at Broad. 

“We found that IDH mutations are like a ticking time bomb that allows brain tumor cells to grow slowly and hide from the immune system while they acquire more dangerous mutations. Once they’ve got these mutations, tumor growth becomes fast and lethal.”  

Bernstein is also chair of the Department of Cancer Biology at Dana-Farber Cancer Institute, a professor in cell biology and pathology at Harvard Medical School, and holds the Richard and Nancy Lubin Family Chair.

Inevitable progression

Gliomas arise from glial cells, which protect and support a healthy nervous system. A substantial proportion of glioma cases are caused by mutations in IDH (isocitrate dehydrogenase).  

“Patients diagnosed with one of these tumors in their 20s or 30s often die in their 40s or early 50s,” said study co-first author L. Nicolas “Nick” Gonzalez Castro, a postdoctoral scholar at Broad, a neuro-oncologist at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Massachusetts General Hospital. “So, there's a great need to understand these tumors better.” 

In IDH-driven gliomas, the mutated IDH enzyme fosters the addition of methyl groups to the cells’ DNA. These chemical changes alter the expression of genes without modifying the underlying DNA sequence. Previous work suggests these epigenetic changes can shift the activity of specific cancer genes, and the new work also reveals details on those shifts. 

Switching drivers, shifting identity

The researchers explored the progression of the tumors by comparing the genetic and epigenetic profiles of both early-stage, low-grade and later-stage, high-grade ones. For this analysis, they used samples from 30 glioma tumors as well as data from much larger sets of tumors represented in The Cancer Genome Atlas and the Glioma Longitudinal Analysis Consortium.

The team found that as glioma tumors progress from early to late stages, they acquire new, cancer-driving mutations to their DNA, while losing the excessive methylation as the cancer cells proliferate. 

“The tumor starts with an epigenetic driver and then switches to genetic drivers,” said Jingyi Wu, a study co-first author who conducted the work while at Broad and Dana-Farber and will soon join the faculty of Beth Israel Deaconess Medical Center and Harvard Medical School. 

The researchers add that a similar mechanism may underlie other initially slow-growing cancers that are also caused by excessive methylation before turning deadly, such as colon cancer. 

Their analysis also revealed a shift in the identity of the tumor cells. Most cells in the early-stage tumors resembled those that specialize in generating glia. Later-stage tumors, however, were dominated by cancer cells that look like more primitive neural progenitor cells (NPCs). 

“We know that in normal brain development, NPCs are more proliferative,” Wu said. “That’s also true of the NPC-like cells in high-grade glioma tumors.” 

Improving therapy

Moreover, the researchers discovered a new effect of the excessive methylation. They determined that this epigenetic change represses the immune system’s tumor-fighting interferon response, and suggest that treatment with a methylation-reducing compound may restore it. 

The researchers say these findings suggest patients with low-grade IDH gliomas could potentially benefit from immunotherapy, which seeks to overcome cancer’s repression of the immune system. Clinical trials are now underway to test IDH inhibition alongside immunotherapy. 

The findings may also help explain why reducing methylation, which is what the new IDH inhibitor vorasidenib does, only works early in the disease. Later in the disease, other genetic drivers that are not targeted by the drug take over. 

What’s more, by identifying the mechanism of the tumors’ transformation from low-grade to high, the research has found a focus for future drug development. “At all stages, at all grades, that’s what we should target,” Gonzalez Castro said.