A new study from City of Hope researchers has identified how mapping the genetic material surrounding chromosomes in brain tumors may help physicians develop more personalized therapies for patients with glioma, a type of brain cancer.
The findings, published in Nature Communications, provide foundational knowledge that could improve precision medicine approaches and potentially reduce the risk of cancer recurrence.
Led by David Craig, PhD, professor and chair of the Department of Integrative Translational Sciences at City of Hope, and Gabriel Zada, MD, a neurosurgeon at Keck Medicine of USC and codirector of the USC Brain Tumor Center, the research team analyzed tumor and normal DNA, as well as RNA, from patients with glioma. Using spatial transcriptomics – a technique that measures and maps gene activity within tumor tissue – the researchers identified how clusters of tumor cells with shared ancestry acquire distinct mutations and adapt to their microenvironment.
One of the study’s major findings was the identification of extrachromosomal DNA, or ecDNA, in several brain tumor samples. These small circles of DNA, which exist outside the main chromosomes, were found to drive rapid oncogene amplification and enable tumor cells to adapt and proliferate, even under selective pressure from therapies. The presence of ecDNA, especially when coupled with cancer-associated proteins such as EGFR and p53, was linked with hypoxic (low oxygen) tumor environments, which have been associated with cancer progression, treatment resistance, and poor clinical outcomes.
The researchers also demonstrated that integrating spatial transcriptomics with DNA sequencing can reveal how subclonal populations of tumor cells evolve and contribute to tumor heterogeneity. This approach may help physicians identify new therapeutic targets and inform strategies to prevent disease recurrence.
“By uncovering these mechanisms, we are paving the way for more precise and effective treatments tailored to the unique biology of each patient,” said Dr. Craig in a press release.
The initial cohort included 11 glioma samples of varied pathology, with a replication cohort of 6 high-grade glioblastomas. The researchers identified focally amplified ecDNA in 4 of the initial gliomas and validated these findings in the replication cohort, where additional ecDNA subclones were observed. The dynamic nature of ecDNA may explain why some brain tumors are particularly difficult to treat and prone to recurrence.
While further research is needed, these findings suggest that mapping the spatial and genetic landscape of tumors can provide insights for the development of personalized cancer therapies. The framework described in this study may be applied to other cancer types in the future.
Disclosures: The study was supported by the National Center for Advancing Translational Science of the U.S. National Institutes of Health (KL2TR001854). Disclosures are available in the original publication.
Source: Nature Communications, EurekAlert
