Investigating How Brain Tumors Evolve

Daniel Brat, MD, PhD, the chair and Magerstadt Professor of Pathology. — Daniel Brat, MD, PhD, the chair and Magerstadt Professor of Pathology, was a co-author of the study.

A new study published in Nature sheds light on how two major types of brain tumors progress over time, offering critical biological insights that could guide treatment decisions.

The findings represent a significant advance in understanding IDH-mutant gliomas, said Daniel Brat, MD, PhD, the chair and Magerstadt Professor of Pathology, who was a co-author of the study.

The research builds on nearly two decades of work that began with The Cancer Genome Atlas (TCGA), a landmark effort launched in 2006 to comprehensively characterize cancers at the molecular level. According to Brat, TCGA transformed oncology research by creating a rich molecular resource, but was limited to data collected from initial tumor samples.

“The problem with TCGA is that it’s a one-time-only data set,” Brat said. “Which tells us about the primary disease, and we’ve learned a lot about it.”

To better understand the molecular features of how brain tumors progress over time, Brat and his international collaborators studied two types of IDH-mutant glioma tumors, astrocytomas and oligodendrogliomas.

Using DNA sequencing and other genetic technologies on tumor samples from 183 patients with IDH-mutant gliomas, the investigators found that IDH-mutant astrocytomas and oligodendrogliomas follow distinct evolutionary paths. According to the findings, astrocytomas tend to progress by acquiring oncogenic gene amplifications that drive disease progression, while oligodendrogliomas show a different pattern characterized primarily by accumulating genetic mutations.

“What they found in a nutshell is that IDH mutant astrocytomas progress by having gene amplifications introduced that are oncogenic and cause biologic and clinical progression, whereas oligodendrogliomas, on the other hand, don’t have those amplification events and have more of a mutational profile,” Brat said.

The study also examined the effects of temozolomide, a chemotherapy commonly used to treat these tumors. While effective, the treatment can lead to additional mutations in some patients, Brat said.

“Probably 30 percent of IDH-mutant gliomas become hypermutant, and those hypermutations are believed to actually cause more aggressive clinical course at recurrence,” said Brat, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

According to Brat, the findings help separate genetic changes caused by therapy from those that occur as part of the tumor’s natural progression, potentially informing future treatment strategies.

More broadly, the work helps answer longstanding questions about tumor grading and risk assessment in IDH-mutant gliomas, Brat said. Earlier studies defined these tumors as distinct molecular entities, but clinicians lacked a detailed understanding of how they progressed or how best to identify high-risk patients.

“This is an important paper because it’s the first to demonstrate how these IDH mutant gliomas progress biologically and clinically over time,” said Brat, who is also a member of the Center for Human Immunobiology (CHI).

The findings have already influenced efforts to develop molecular-based grading systems for astrocytomas and oligodendrogliomas, Brat said. Traditional grading approaches have relied largely on what pathologists can observe under a microscope, but molecular characteristics may provide more accurate information.

“Now in the molecular era, we can say these molecular features are prognostic and actually better than morphologic features and should be incorporated into our grading schemes,” Brat said.

Looking ahead, the study could help inform patient care, Brat said. Better molecular definitions may help clinicians decide when patients can be treated with targeted IDH inhibitors and when they need more intensive therapies.

“This study has a real-world impact, because it affects the way patients are treated dramatically, especially those who have low-risk disease, and we feel like we’ve defined low-risk disease from the pathologic perspective now,” Brat said.

For Brat, who has contributed to major advances in glioma classification since the mid-2000s, the publication marks an important milestone in a long scientific journey.

“I wouldn’t say the story’s ended, but this is a major punctuation in it,” he said.

He added that the study highlights the power of scientific collaboration across institutions and countries.

“It really takes a group effort, both institutionally, between different academic medical centers and across the globe,” Brat said. “It’s really a community-based effort.”

The study was supported by the National Cancer Institute (NCI), the German Research Foundation and the Dutch Cancer Society.

Legal Disclaimer:

EIN Presswire provides this news content "as is" without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the author above.