Study IDs ways IDH-related brain tumors become more aggressive
Genetic changes may explain why these gliomas grow faster over time
Researchers have uncovered genetic changes that may explain why certain brain tumors, known as gliomas, that are associated with IDH gene mutations start off as slow-growing but eventually become more aggressive.
Early on, the tumors seem to be promoted by a type of DNA modification called methylation that helps the cells escape detection from the immune system. This gives them room to acquire genetic mutations and take on a faster-growing, more aggressive profile later on, according to the team, led by researchers from the Broad Institute of MIT and Harvard in Massachusetts.
The scientists say their findings emphasize the importance of early disease detection.
“This recognition that IDH-mutant gliomas of different stages are driven by distinct molecular mechanisms … has important therapeutic implications,” the team wrote, noting that “progressed or relapsed tumors … will be less likely to respond to interventions.”
Early detection may allow patients sooner access to treatments — such as the recently approved oral IDH inhibitor Voranigo (vorasidenib) — that are only effective when the tumor is still in its earlier stages.
The study, “Evolving cell states and oncogenic drivers during the progression of IDH-mutant gliomas,” was published in the journal Nature Cancer.
Studying why IDH-linked brain tumors grow slowly, then become aggressive
Gliomas are a type of brain tumor that develop from glia, a family of nervous system support cells. A significant proportion of glioma cases are associated with mutations in the IDH gene, which encodes the production of an enzyme of the same name that’s involved in cell metabolism.
IDH-associated gliomas often start by growing slowly — thus called low-grade — but they eventually take a more aggressive course, or turn high-grade, and may become fatal.
“Patients diagnosed with one of these tumors in their 20s or 30s often die in their 40s or early 50s,” L. Nicolas Gonzalez Castro, MD, PhD, one of the study’s first authors and a postdoctoral scholar at the Broad Institute, said in an Institute news story. Castro also is a physician at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Massachusetts General Hospital.
One key problem, according to the scientists, is that the mechanisms underlying the shift from slow to fast growth are not well understood. Now, the team set out to explore how this change happens.
“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 Brad Bernstein, MD, PhD, a senior author of the study who also serves as a Broad Institute researcher and a professor at Dana-Farber and Harvard Medical School.
It’s known that a mutant IDF enzyme induces certain epigenetic changes in tumor cells. Epigenetics refers to chemical alterations that affect gene activity, but don’t directly alter the DNA sequence.
In the case of IDF-associated gliomas, there’s an excess of an epigenetic modification called methylation that’s thought to alter the activity of cancer-related genes to promote tumor growth.
The scientists were particularly interested in understanding further whether any particular genetic and epigenetic changes would explain how gliomas become more aggressive over time.
By profiling cells taken from IDH-mutant gliomas — both low-grade and high-grade ones — the team found that tumor progression appeared to be linked to a switch from epigenetic to genetic drivers.
Specifically, as gliomas progressed from low- to high-grade, they developed new cancer-accelerating DNA mutations while losing the excessive methylation that had been observed earlier.
Moreover, low-grade tumors were composed mainly of cells with a profile similar to glial precursor cells, but they seem to be reprogrammed later to have a profile more like nerve cell precursors. Nerve cell precursors are faster growing, which the researchers indicated could help explain the more aggressive disease course at that stage.
Researchers note most treatments only work early on
The team also discovered that excessive methylation in glioma cells seemed to suppress the immune system’s ability to kill off the tumors, allowing them to ultimately progress to become high-grade.
“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,” Bernstein said. “Once they’ve got these mutations, tumor growth becomes fast and lethal.”
These findings highlight the promise of treatments that reduce methylation for treating IDH-related glioma. However, they also help explain a drawback of the approach.
According to the researchers, such treatments will only work early in the disease course when methylation is the main tumor driver. Once other genetic drivers take over, the medications won’t be able to target those changes. The approved therapy Voranigo is cleared for use in patients with low-grade gliomas.
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.
The researchers also believe immunotherapy, which helps boost the immune system’s ability to kill cancer cells, could benefit glioma patients. That’s a strategy that’s being tested in clinical trials.
Overall, “our findings explain how these slow-growing tumors may progress to lethal malignancies and have implications for therapies that target their epigenetic underpinnings,” the researchers wrote.
Beyond gliomas, the researchers note that their findings may have relevance for other types of tumors that start off growing slowly and are driven by excessive methylation, such as those seen in colon cancer.
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