Understanding the genomic complexities of glioblastoma tumors microbiologystudy

The genetic makeup and structure of glioblastoma tumors can shift dramatically across different regions of a single tumor, according to a Northwestern Medicine study published in Science Advances.

Glioblastoma, the most common primary malignant brain tumor, currently has a five-year survival rate of only 6.9%, according to the National Brain Tumor Society. Despite evolving therapy strategies, glioblastoma is extremely treatment-resistant, with an average length of survival of only eight months.

Part of the reason glioblastoma is so difficult to treat is due to the tumor’s ability to rapidly mutate its DNA, according to Feng Yue, Ph.D., the Duane and Susan Burnham Professor of Molecular Medicine and senior author of the study.

“In our previous research, we reported that genes are expressed differently in different locations on the same tumor,” said Yue, who is also a professor of Biochemistry and Molecular Genetics, of Pathology and director of the Center for Advanced Molecular Analysis. “But in this latest study, we go deeper into the mechanism to try to explain why they’re expressed at different levels in different spots within the same tumor and across different patient samples.”

In the current study, Yue and his collaborators utilized Hi-C sequencing—a technique that analyzes the three-dimensional folding of the genome—on nine glioblastoma patient samples and three healthy ones.

They found that glioblastoma genome structure and expression varied widely between patients and even in different locations within the same tumor, according to the findings.

“We identified glioblastoma-specific genome folding patterns that are different from normal samples and each individual patient also has a different structure,” Yue said. “And to make things more complicated, even within the same tumor, in the same patient at different spots, they have different genome structures.”

The findings highlight the complexities of glioblastoma tumors and may prove useful in developing treatment strategies, Yue said.

“This heterogeneity of genetic mutations and aberrant oncogene dysregulation is one of the main reasons why treatment fails,” Yue said. “Therefore, we should target the abnormalities shared across the whole tumor, rather than those that appear in only one spot.”

Moving forward, Yue and his laboratory will work to identify strategies to alter genome structure and regulation to support treatment, he said.

“In this study, we also identified key distal regulatory elements that control those important oncogenes or tumor suppressors. Whether we can find a way to manipulate these elements and further reverse the cancer-specific dysregulation is the next step,” said Yue, who is also the founding director of the Center for Cancer Genomics at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “We are pretty sure that the 3D genome folding plays an essential role during the process.”