Short Summary: Small fragments of DNA that are not part of chromosomes (where DNA is usually packaged in human cells) – which were thought to be inconsequential and extremely rare in human cancers – have been found in high-frequencies in brain tumors, but not normal cells. These circular stretches of “extrachromosomal” DNA were revealed to have a high-likelihood of driving tumors and making them difficult to treat. This is a new discovery that has the potential to significantly change the way we view, understand, and treat cancer based on where culprit, cancer-fueling genes are found.
It is widely understood that cancer is often the result of changes that occur to certain genes. In different cancers, one or more genes can be found to be altered through a mutation (or change to the DNA sequence), an extra copy, a deleted copy, or other mistakes that occurred during a cell’s replication process. And because genes are typically found on chromosomes, this is often where cancer researchers assumed any cancer-causing genes (or oncogenes) resided.
But now researchers, funded by the Defeat GBM Research Collaborative, have made a startling and paradigm-shifting discovery that may upend how the science and medical fields understand what goes wrong with genes in cancer, particularly brain tumors. This could also lead to new ways to prevent and treat cancer.
The new findings, published online today in the leading scientific journal Nature, show that short, circular fragments of DNA containing oncogenes, that are separate from the DNA found in chromosomes, are present in a wider variety of cancers than previously thought, including approximately 90% of brain tumors. These small DNA particles are called, “extrachromosomal circular DNA” or ecDNA, and are almost never found in healthy, normal cells.
Importantly, the researchers found that oncogenes (again cancer-fueling genes) are significantly more likely to be found on ecDNA than on chromosomes. In other words, ecDNA plays a far bigger role in the growth, diversity and drug resistance of cancer cells than genes housed on chromosomes in such tumors. The team then took this one-step further and also demonstrated that tumors are more diverse (or heterogeneous) when oncogenes are active on ecDNA than on chromosomes, accelerating evolution in tumors that makes them more complex and harder to treat. This is because, unlike normally when DNA in chromosomes is passed down to “daughter cells” equally when cells replicate and divide (as they are constantly doing in the human body) through an orderly directional process, the circular less complex nature of ecDNA allows for genes to be amplified quickly and passed down in a more random manner, enabling tumors to more rapidly acquire and pass-on high levels of cancer-promoting oncogenes, and to do so in a way that greatly enhances cell to cell variability, enabling tumors to rapidly evolve.
Until this new study, ecDNA was thought to be extremely rare not only in normal cells, but even in tumors; as it was estimated that ecDNA could be found in less than 2% of all cancers. But the leader of this new discovery, Dr. Paul Mischel of the Ludwig Institute for Cancer Research and the University of California, San Diego, had previously shown that ecDNA plays a central role in the drug resistance of certain brain tumors. Specifically, they found that EGFR mutations on ecDNA may enable GBMs to become resistant to targeted cancer therapy. This came as a surprise because, for decades, cancer biologists had focused more on which genes promote cancer rather than where those genes are located. Genomic technologies too evolved along lines that favored this type of analysis. Although a few cancer biologists in the 1960s had described the presence of ecDNA in some tumor cells, they lacked the tools to quantify ecDNA, so the phenomenon had long been considered rare and inconsequential to the development of cancer. (So inconsequential, in fact, that the National Cancer Institute’s comprehensive glossary of cancer genetic terms doesn’t currently even include an entry for ecDNA.)
“It occurred to us after we made the observations published in 2014 that maybe ecDNA is a lot more common and consequential than anyone thought,” says Mischel. “Understanding how tumor cells evolve and how they increase the copy number and variability of their drivers is likely to yield some pretty important clues about the fundamental biology of cancer and how we might be able to target it,” said Dr. Mischel.
Dr. Mischel and his colleagues’ new paper now shows that ecDNA is very common in a wide variety of cancer types and that it may contribute greatly to malignant behavior, particularly in brain tumors, by driving the complex and diverse evolution of tumor cells, which make advanced cancers so difficult to treat.
Critically, Dr. Mischel and his colleagues are now working to unearth the molecular mechanisms involved in the genesis and maintenance of ecDNA and exploring how ecDNA levels change in response to changes in the tumor’s internal environment. This could help uncover how ecDNA formation can be stopped before it drives tumor evolution and diversity, making cancers like glioblastoma extremely difficult to treat.
Dr. Mischel credited the funding he received through the Defeat GBM Research Collaborative, as well as critical interactions with other researchers the Collaborative fostered, as essential to this new discovery.
“We are grateful to [NBTS] and the Defeat GBM team for all of your support which was crucial for making this work happen,” said Dr. Mischel.
Other researchers, in addition to Dr. Mischel, who are involved in the Defeat GBM Research Collaborative who were also involved in this work are Drs. Webster Cavenee and Frank Furnari – both also from Ludwig Cancer Research. Dr. Robert Wechsler-Reya of Sanford-Burnham Medical Research Institute, a former NBTS grantee and current research advisor, was also part of the study.
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