When a cancer cell’s DNA becomes damaged, pieces can break away from the chromosomes and drift away, like an iceberg breaking off a glacier. Just as icebergs are a threat to ships and their crews, these scattered pieces of DNA have a huge impact on tumor progression and treatment resistance, posing a major threat to doctors and cancer patients.
Scientists at the Sanford Burnham Prebys Medical Discovery Institute and their colleagues published their findings on May 28, 2026. genomic medicine We demonstrated striking similarities between tumor samples characterized by these linear DNA fragments and research models developed using these tumor samples. This tight match gives scientists greater confidence as they use these models to learn how to better diagnose and treat cancers caused by these DNA debris spots.
In 1965, researchers first documented what is now known as a circular extrachromosomal DNA element (ecDNA) because of its round shape. Then, in 1978, scientists discovered in mice that ecDNA made cancer cells more resistant to chemotherapy drugs.
More recent studies have found that ecDNA occurs very frequently, especially in aggressive tumor types. And the presence of these missing DNA loops is associated with worse clinical outcomes. ”
Dr. Lucas Chavez, Associate Professor, Cancer Genomics and Epigenetics Program, Sanford Burnham Prebys
Chavez and his team wanted to study how ecDNA affects pediatric brain tumors using a common research model created by transplanting tumor cells from human patients into mice, but the field lacked evidence about how well the resulting mouse models matched human tumors.
“The research models created in this way required a long time and a great deal of care to generate, so it was important for us to determine their validity for studying ecDNA behavior,” said Rishaan Kenkure, a research scientist in the Chavez lab and lead author of the study.
These patient-derived xenograft (PDX) models are of general interest for their ability to mimic human disease and enable both basic research and testing of new potential treatments. To confirm that this was true for cancer cells with ecDNA, the researchers analyzed nearly 300 pediatric tumor samples across 31 cancer types and compared them to a PDX model created from each sample.
Scientists found ecDNA in just under a third of the samples. The ecDNA in these models contained extra copies of genes that can cause cancer, known as oncogenes. And which cancer genes had extra copies mirrored a pattern found in a large study of thousands of childhood tumors.
The scientists then narrowed down the group that had access to genomic sequence data for both human tumor samples and the resulting PDX models.
“In more than 80% of PDX models, the presence of ecDNA was consistent with the primary tumor,” said Chavez, senior and corresponding author of the manuscript. “The ecDNA sequences were also nearly identical between these pairs.”
After confirming that similar numbers of extra cancer gene copies were present in primary tumors and their respective PDX models, the research team turned to methods that could confirm the effects of ecDNA on individual cells within a tumor.
In one of the two pairs of brain tumors and corresponding PDX models studied using single-cell sequencing, nearly all cells within the tumor had ecDNA, as did the PDX model. In the other pair, fewer than 1 in 10 cells had ecDNA, whereas the PDX model was characterized by the presence of these ecDNA in virtually all cells.
“We found that ecDNA-positive cells derived from human tumors grew exclusively into the PDX model, even though they comprised only a small fraction of the tumor population,” Kenkre said. “We could speculate that, at least for this particular pair, ecDNA could provide a selective advantage as PDX models are developed.” These findings further support the idea that ecDNA-positive tumor cells may play an important role in promoting tumor growth and recurrence in human patients.
The authors conclude that the similarities observed between the tumor and PDX models suggest that this model is an effective tool to continue learning how ecDNA promotes cancer cells and how to stop it.
The research team plans to use the PDX model to study how ecDNA within cancer cells evolves over time as the cells try to adapt to common treatments such as chemotherapy and radiation.
“Our goal is to gain new insights into ecDNA-related therapeutic resistance and uncover new potential therapeutic targets for childhood cancers,” said Professor Chavez.
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Reference magazines:
Kenkre, R. others. (2026). Extrachromosomal DNA conservation and clonal behavior in patient-derived xenograft models of childhood cancer. genomic medicine. DOI: 10.1186/s13073-026-01676-0. https://link.springer.com/article/10.1186/s13073-026-01676-0
