The Paradigm Shift of Tumor Evolution

Extrachromosomal oncogene helps drive tumor evolution and heterogeneity.

Investigators discovered that extrachromosomal DNA (ecDNA) plays a significant role in growth, diversity, and drug resistance of cancer cells, and is much more common in tumors than previously believed.

In a study published in Nature, investigators found that ecDNA is a key feature in nearly half of all types of tumors, and it encodes multiple copies of cancer-driving genes.

“We’ve discovered something fundamental about how cancers diversify and evolve,” said investigator Paul Mischel. “This is an essential rethinking about what goes wrong with genes in cancer.”

For the study, the investigators integrated different technologies, including bioinformatics, genomics, and classical cytogenetics, to detect, quantify, and analyze ecDNA from 17 different types of cancer.

The results of the study showed that ecDNA was present in 40% of the tumor cell lines, but extremely rarely in normal cells. Upon closer examination of patient-derived models of brain tumors, the investigators found that nearly 90% carried ecDNA.

Through a collaborative effort, the investigative team found that oncogenes are more likely to occur on ecDNA than on chromosomes. Next, they quantitatively modeled the findings and verified the model’s predictions through experiments conducted on tumor samples derived from patients.

The findings indicated that tumors are more heterogeneous when oncogenes are amplified on ecDNA instead of on chromosomes, which allows them to more rapidly achieve and maintain high levels of cancer promoting genes.

The ecDNA differs from chromosomes in that they are parceled out randomly to daughter cells when a tumor cell divides, according to the study. This means that any cell in the tumor could have no ecDNA in its nucleus or be completely crammed; the more the variation in their number, the greater the heterogeneity of cells in a tumor. The authors noted that this cellular diversity allows tumors to be more resistant to environmental challenges, such as cancer treatment.

The current work was based on prior findings from their study published in Science in 2014. In the previous study, the authors found that ecDNA played a key role in the drug resistance of certain brain tumors. The findings were a surprise because cancer biologists have focused for more than a decade on which genes promote cancer rather than where those genes were located.

“It occurred to us after we made the observations published in 2014 that maybe ecDNA is a lot more common and consequential than anyone though,” Mischel said. “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.”

Currently, the investigators are working to identify the molecular mechanisms involved in the genesis and maintenance of ecDNA, as well as examining how the levels of ecDNA changes in response to changes in the tumor microenvironment.