A research team led by Professor Paul Mischel from the Ludwig Cancer Institute at the University of California, San Diego found that a large number of oncogenes are not on the chromosome, but will fall off and form extrachromosomal DNA (ecDNA).The article was published in the journal Nature under the title "Circular ecDNA promotes accessible chromatin and high oncogene expression". This study discovered the structure and basic functions of ecDNA, which laid an important foundation for subsequent basic and applied research.
Cancer is a genetic disease, which is caused by the loss of the function of cancer suppressor genes and the hyperfunction of proto-oncogenes. In the era of high-throughput sequencing, the cancer genome has been clearly identified. But where is the oncogene? Generally, genes are on the chromosome. However, the research team found that a large number of oncogenes are not on the chromosome, but will fall off from the chromosome and become a small type of DNA called extrachromosomal DNA (ecDNA). This ecDNA is widespread in tumors, accounting for about one-third of all tumor cases. Its copy number is often high and highly dynamic, which changes with cell replication and drug treatment. Therefore, the existence of ecDNA is an important factor driving cancer heterogeneity and a factor leading to cancer drug resistance.
The research results mainly include the following aspects
First, ecDNA is circular. Combining methods such as next-generation genome sequencing, optical mapping, scanning electron microscopy, transmission electron microscopy, and 3D structured illumination microscopy, it has been found that ecDNA and classical eukaryotic chromosomes are different in spindle shape and are circular DNA molecule. Second, ecDNA transcribes a large number of oncogenes. ecDNA can be transcribed into mRNA, and ecDNA can often reach tens or even hundreds of copies. Therefore, these high-copy ecDNAs can transcribe a large number of oncogene products, thereby promoting tumor progression. At the same time, the chromatin of ecDNA is highly open. Every cell in the body carries a proto-oncogene. Because of the presence of heterochromatin in the nucleus of human cells, genes cannot be expressed, including some oncogenes. On ecDNA, the structure of chromatin is relatively open. Almost all of these genes are successfully transcribed. Therefore, once the proto-oncogene is shed from the chromosome to form this circular ecDNA, it can be expressed in large quantities. DNA sequences in cells interact with each other due to the folding of DNA, and then regulate gene expression. The frequency of this interaction decreases as the distance between the two pieces of DNA increases. The circular ecDNA enables DNAs that were originally far apart to be ligated together, enabling ultra-long distance interactions.
For the first time, this study positively analyzed the structure and basic functions of the ecDNA on which the oncogene is located, laying an important foundation for subsequent basic and applied research. Including the mechanism of ecDNA production, replication, and movement, as long as we find a mechanism for tumors to maintain ecDNA homeostasis, we even have a way to develop a universal anti-tumor strategy that targets ecDNA directly for anti-tumor treatment. However, there is still a long way to go before the goal is achieved, and they will continue to move towards this goal.