A new study has revealed how rogue rings of DNA, known as extrachromosomal DNA (ecDNA), play a critical role in the earliest stages of glioblastoma, the most aggressive adult brain cancer. The research, published in Cancer Discovery, shows that these DNA circles carrying cancer-promoting genes can appear before a tumor has fully formed, shaping how glioblastoma evolves and why it is so resistant to treatment.
Glioblastoma has long been one of the most challenging cancers to treat, with a median survival of only 14 months and little progress over the past decades. Understanding how ecDNA fuels tumor growth may open up new paths for earlier detection and intervention.
Early and potent drivers
Unlike chromosomal DNA, ecDNA floats freely within a cell’s nucleus. It can carry powerful oncogenes, replicate quickly, and be passed on unevenly when cells divide. This randomness generates striking tumor heterogeneity, one of the key reasons glioblastoma adapts and resists therapy.
In the new study, researchers analyzed samples from 94 treatment-naive glioblastomas. They discovered that oncogene amplification almost always occurred on ecDNA. EGFR ecDNA in particular emerged before clonal tumor expansion, conferring strong fitness advantages and driving tumor growth.
The team also showed that both wild-type and variant EGFR ecDNA often coexist in tumors. Variants such as EGFRvIII consistently arose from pre-existing wild-type EGFR ecDNA, occurring early and reaching high levels.
Archaeology of a tumor
To untangle how ecDNA evolves across time and tumor space, the team developed a new modeling approach called SPECIES (spatial–temporal computational model of ecDNA-positive tumors). By integrating genomic data, DNA FISH imaging, and transcriptional measurements with simulations, SPECIES allowed the researchers to reconstruct ecDNA’s evolutionary trajectories.
The approach revealed two groups of EGFR tumors—those with premalignant accumulation of ecDNA, likely contributing to tumor initiation, and those with few ecDNAs early in development. “The emergence of high-level EGFR amplification facilitates subsequent oncogenic mutations to arise on ecDNA, such as EGFRvIII, as well as point mutations such as EGFR p.A289V,” the paper explained.
These insights extend earlier work linking EGFR amplification to glioblastoma initiation but add new detail by accounting for ecDNA dynamics.
Distinct paths for different oncogenes
The study also showed that not all ecDNA follows the same evolutionary playbook. Tumors with ecDNA carrying PDGFRA—the gene encoding platelet-derived growth factor receptor alpha, a tyrosine kinase receptor involved in cell growth and development—often co-amplified other oncogenes on the same ring and displayed different growth patterns compared to EGFR-driven tumors.
This finding suggests that the oncogenic cargo of ecDNA dictates not only how a tumor grows but also how it may respond to therapies.
A window of opportunity
Perhaps most striking is the observation that ecDNA can accumulate before clonal tumor growth, offering a theoretical opportunity for early detection and intervention. “The observation that amplification of wild-type EGFR on ecDNA, followed by mutational processes that give rise to more potent EGFR variants such as EGFRvIII, suggests that there may be a period between initial ecDNA formation and the development of more potent gain-of-function mutagenesis that could be amenable to therapeutic intervention and early cancer detection,” the study concluded.
Liquid biopsies capable of detecting ecDNA in blood or cerebrospinal fluid are under active investigation, though researchers caution that such approaches remain experimental. “Such screenings are highly theoretical currently, however, as we neither know the duration of such a precancerous state, nor would we know whom to screen and when, highlighting the need for further investigation.”
Implications for treatment
Glioblastoma has resisted targeted therapies for decades. Drugs directed against EGFR have largely failed in clinical trials, partly because of intratumor heterogeneity. The study highlights how ecDNA contributes to this problem. “Intratumor heterogeneity of EGFRvIII contributes to the failure of EGFR-targeted therapies, although chimeric antigen receptor T cells targeting both EGFRvIII and EGFRwt have recently shown promise,” the authors wrote.
These findings suggest that incorporating ecDNA profiling into clinical trials could improve how patients are stratified and how therapies are designed.
By mapping ecDNA’s spatiotemporal evolution, the study reframes glioblastoma as a disease where rogue DNA circles act as early and powerful drivers. The researchers emphasized that further studies in larger patient cohorts will be needed to validate these findings and test whether targeting ecDNA dynamics can improve outcomes.