Recurrent brain tumors undergo unique genetic changes after treatment

When patients are diagnosed with certain brain tumors, one of the biggest unanswered questions is what happens when the cancer returns. Among those are IDH-mutant gliomas, a group of brain tumors that invariably recur despite advances in treatment.

Now, scientists from The Jackson Laboratory (JAX), Yale University, and collaborators across 10 countries report that these gliomas undergo unique genetic changes when they return after treatment.

The findings, published today in Nature, could help researchers understand why these tumors become resistant to therapy and point toward more tailored treatment approaches in the future.

IDH-mutant gliomas are defined by mutations in a gene called isocitrate dehydrogenase (IDH). These tumors primarily affect patients in their 30s and 40s, making them particularly devastating. Although many patients live for years after diagnosis, these tumors almost always recur and eventually stop responding to treatment.

The study drew on data from the international Glioma Longitudinal Analysis (GLASS) Consortium and included 183 patients whose tumors were sampled both before and after recurrence, allowing researchers to directly compare how the cancers changed over time. Researchers analyzed samples collected through more than 500 surgeries spanning North America, Europe, Asia, Australia and South America.

"IDH-mutant gliomas are rare, which makes them challenging to study. Through this international collaboration, we were able to gather enough samples to characterize the most common ways each type of IDH-mutant glioma changes when it recurs," said study author Frederick Varn, a JAX assistant professor who co-led the research.

The unique dataset allowed researchers to follow tumors over time and examine how they changed after treatment and recurrence. For example, the chemotherapy drug temozolomide appeared to leave distinct genetic fingerprints in recurrent tumors. This finding highlights how standard treatments may influence the genetic changes tumors acquire as they recur.

The most striking differences emerged in how the tumors changed over time despite sharing the same defining IDH mutation. One subtype of IDH-mutant glioma, called oligodendroglioma, tended to acquire new mutations in genes that help drive tumor growth. By contrast, a different subtype, called astrocytoma, was more likely to undergo large-scale chromosomal changes, gaining and losing large stretches of DNA as the disease progressed.

Oligodendroglioma and astrocytoma are distinct tumor types, despite sharing the IDH mutation. This study shows that differences that exist when the tumor is first detected can set the stage for what happens after they are treated."

Frederick Varn, assistant professor, Jackson Laboratory

Some of the genetic changes in recurring tumors appeared to be associated with poorer outcomes. In astrocytomas, large-scale chromosomal abnormalities, including the duplication of entire sets of chromosomes and instances in which chromosomes broke apart and reassembled, were linked to shorter survival after recurrence. In oligodendrogliomas, some of the new genetic changes that emerged as the tumors recurred, including changes linked to uncontrolled cell growth, were also associated with poorer outcomes.

In 2024, the FDA approved the IDH inhibitor vorasidenib for certain patients with these tumors, marking a major advance for the field. While this study focused on the changes tumors undergo after radiation and chemotherapy, its findings can be applied to better tailor treatment approaches to specific glioma types and to the genetic changes they are likely to acquire as they evolve over time.

"Our results and datasets provide a reference that helps understand how current and new therapies alter tumor behavior. Ultimately, we hope this will enable us to not just observe but to direct tumor behavior and make therapies more effective that way," said Roel Verhaak, Ph.D., vice chair for research and professor of neurosurgery at Yale School of Medicine.

The study was conducted through the international GLASS Consortium and included researchers from institutions across North America, Europe, Asia and Australia. Funding was provided by the National Institutes of Health and additional public, philanthropic and institutional sources listed in the study.