“Rogue” DNA Ring reveals Earliest Secrets of Glioblastoma Aggression
New research has uncovered a crucial role for extrachromosomal DNA (ecDNA) – frequently enough described as “rogue” DNA – in the progress and progression of glioblastoma, an aggressive form of brain cancer. The study, led by researchers at the Barts Cancer Institute, queen Mary University of London, and collaborators, reveals that ecDNA appears very early in cancer evolution, perhaps even before tumor formation in some patients, and substantially influences tumor aggressiveness.
The analysis focused on ecDNA rings, circular pieces of DNA separate from the chromosomes, and found that the majority contained the EGFR gene, a well-known driver of cancer growth. Importantly, these EGFR containing ecDNA structures often accumulate further genetic alterations, such as the EGFRVIII variant, which is linked to increased aggressiveness and resistance to therapy.
“This subtle mechanism shows that there may be a window of opportunities to detect and treat diseases between the first appearance of EGFR ecDNA and the emergence of this more aggressive variant,” explains Dr. Magnus Haughey, a postdoctoral researcher and co-author of the study. Researchers suggest that developing sensitive tests, potentially blood tests, to detect early EGFR ecDNA could allow for intervention before the cancer becomes more difficult to treat.
The research also confirms that ecDNA can carry multiple cancer-driving genes together, each impacting how tumors evolve and respond to treatment.This finding underscores the potential for tailoring treatment strategies based on a tumor’s specific ecDNA profile.
Future research will focus on understanding how different treatments affect the number and types of ecDNA present in glioblastoma, and investigating the role of ecDNA in other cancer types.
According to Dr. Charlie swanton of the Francis Crick Institute and Cancer Research UK, the findings demonstrate that ecDNA isn’t merely a byproduct of glioblastoma, but an active driver of the disease, appearing early and influencing its trajectory. Dr. Paul Mischel of Stanford Medicine added that the work builds on previous findings showing ecDNA can arise both early and late in tumor development, contributing to both initial growth and treatment resistance.
dr. David Scott, Director of the Grand Cancer Challenge, highlighted the importance of supporting this type of essential cancer research, stating that understanding the evolutionary history of ecDNA in glioblastoma is a critical step towards solving some of the toughest challenges in cancer research.
Reference: Noorani, I., Haughey, M., Luebeck, J., Rows, A-S., Frances, E., Pinces, F.,… & Werner,B.(2024). Heterogenous and Evolution Oncogenic Extrachromosomal DNA in glioblastoma.Cancer Discovery. DOI: 10.1158/2159-8290.cd-24-1555
Funding: francis Crick Institute, Cancer Research UK, NIH/National Cancer Institute.
