Cancer is one of the biggest health problems in the world because, unlike some diseases, it is a moving target that is constantly evolving to avoid treatment and resist it.
In a paper published in the online edition of the journal. December 23, 2020 Nature, researchers from the University of California, San Diego School of Medicine and the UC San Diego branch of the Ludwig Institute for Cancer Research, with colleagues in New York and the UK, describe how a phenomenon known as “chromothripsis” breaks chromosomes, which are then reassembled in ways that eventually promoting the growth of cancer cells.
Chromotripsy is a catastrophic mutation event in the history of a cell that involves a massive rearrangement of its genome, as opposed to the gradual accumulation of rearrangements and mutations over time. Genomic rearrangement is a key feature of many cancers, allowing mutated cells to grow or grow faster without being affected by cancer therapies.
“These rearrangements can happen in one step,” said the first author, Dr. Ofer Shoshani, postdoctoral fellow in the laboratory of a co-senior author, dr. Don Cleveland, professor of medicine, neuroscience and cellular and molecular medicine at UC San Medical School Diego.
“During chromotripsy, a chromosome in a cell breaks down into many parts, hundreds in some cases, followed by reassembly in a mixed order. Some parts are lost, while others survive as extrachromosomal DNA (ecDNA). Some of these ecDNA elements promote cell growth. cancer and form small chromosomes called “double minutes”. “
A study published last year by scientists from the UC San Diego branch of the Ludwig Institute for Cancer Research found that as many as half of all cancer cells in many types of cancer contain ecDNA that carries genes that promote cancer.
In a recent study, Cleveland, Shoshani, and colleagues used direct visualization of chromosome structure to identify steps in gene amplification and the mechanism underlying resistance to methotrexate, one of the earliest chemotherapy drugs still widely used.
In collaboration with co-senior author dr. Peter J. Campbell, head of cancer, aging and somatic mutations at the Wellcome Sanger Institute in the UK, team sequenced whole genomes of drug-developing cells, discovering that chromosomal growth begins the formation of ecDNA-carrying genes that resist cancer therapy.
Scientists have also identified how chromotripsis triggers ecDNA production after gene amplification within chromosomes.
Chromotrips converts intra-chromosomal amplifications (internal) to extrachromosomal (external) amplifications and this enhanced ecDNA can then be reintegrated into chromosomal sites in response to DNA damage by chemotherapy or radiotherapy. The new work highlights the role of chromotripsy in all critical phases of the life cycle of DNA-enhanced cancer cells, explaining how cancer cells can become more aggressive or drug-resistant. “
Ofer Shoshani, Ph.D., First Author
Cleveland said: “Our identifications of repeated DNA fragmentation as a driver of cancer drug resistance and DNA repair pathways necessary for reassembly of broken chromosomal parts have enabled the rational design of combination drug therapies to prevent the development of drug resistance in cancer patients. outcome. “
The findings relate to one of the so-called nine major challenges for the development of cancer therapy, a joint partnership between the National Cancer Institute in the United States and Cancer Research UK, the world’s largest independent cancer research and awareness-raising organization.
University of California – San Diego
Shoshani, O., and others. (2020) Chromothripsis initiates the evolution of gene enhancement in cancer. Nature. doi.org/10.1038/s41586-020-03064-z.