The role of extrachromosomal DNA (ecDNA) in advancing tumor progression in glioblastoma (GBM) patients is being investigated by a research team from The Jackson Laboratory (JAX) and Henry Food Health System’s Hermelin Brain Tumor Center. Their preliminary results were published today in Nature Genetics.
They found that ecDNA, which is not found in normal cells, can cause major increases in the expression of oncogenes, and also that many instances of oncogene amplification found in glioma tumors involved ecDNA elements.
"The selective advantage conferred to tumor cells by the regulation of oncogene copy number in ecDNA has not been sufficiently addressed in interpreting results in the laboratory or in clinical trials. Using the GBM patient-derived models carrying ecDNA amplification of the most frequent oncogenes, we are developing and testing novel combination therapies specific for each unique tumor," says Ana C. deCarvalho, Ph.D., assistant professor from Henry Ford Health System.
ecDNA elements were first observed directly under microscopes in cancer cells more than 50 years ago, but it remains unknown how they arise in the first place. Technological limitations have impeded studies of ecDNA in detail, despite a recent publication in Nature suggesting their presence in nearly half of cancers.
Unlike chromosomal DNA, ecDNA is inherited inconsistently as a tumor grows. That is, when a cancer cell divides, the DNA on the chromosomes almost always gets accurately duplicated and remains the same in the daughter cells. But ecDNA inheritance appears to be far more random. Sometimes both daughter cells inherit ecDNA, but sometimes all or most of it will end up in one cell and not the other.
"The process quickly creates important differences between cells within the same tumor, and it helps accelerate the evolution of the cancer," adds Roel Verhaak, professor at JAX. "It provides the cells with more ways to evade stress. Therefore, there's a better chance that at least some of the cells will survive severe stress, such as stresses caused by a chemotherapy or radiation."
One reason ecDNA has been relatively ignored is that it's hard to detect using standard sequencing methods, which don't accurately detect and separate it from chromosomal DNA. But it's now attracting more attention, and the work moving forward will likely help explain why cancers such as GBM are difficult to treat and evolve therapy resistance so rapidly.
"We think targeting ecDNA has huge potential for the development of new cancer treatments" says Verhaak. "We're now working to develop sequencing-based protocols to identify ecDNA more efficiently. The bigger goal is to learn how and why ecDNA elements form. If we can block those mechanisms, we'll have a way to prevent the evolution, and perhaps even the formation, of many cancers."