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In a new study, researchers from research institutions such as the University of California, San Diego, and the University of Cambridge in the United Kingdom described how a phenomenon called chromothripsis destroys chromosomes and then allows them to reassemble in a way that ultimately promotes the growth of cancer cells.
results were published online December 23, 2020 in the journal Nature, under the title "Chromothripsis Drives the evolution of gene geneplification in cancer".
, a professor of cellular and molecular medicine at the University of California, San Diego School of Medicine, and Peter J. Campbell of the University of Cambridge.
images from Nature, 2020, doi:10.1038/s41586-020-03064-z.
chromosomal fragmentation is a catastrophic mutation event in cell history involving large-scale rearms of their genomes, rather than gradually re-platooning and mutations over time.
is a key feature of many cancers, allowing mutant cells to grow or grow faster and not be affected by cancer therapies.
can occur in one step," said Dr. Ofer Shoshani, lead author of the paper and a postdoctoral researcher at Cleveland Labs.
during chromosomal division, one chromosome in a cell is crushed into many fragments, in some cases hundreds, and then reassembled in a disruptive order.
some fragments will be lost, while others will persist as extra-chromosomal DNA (extra-chromosomal DNA, ecDNA).
some of these ecDNA promotes the growth of cancer cells and forms tiny chromosomes called 'double minutes'.
a study published last year, researchers found that up to half of all cancer cells contain ecDNA that carries the cancer-promoting gene.
the new study, Cleveland, Shoshani and colleagues made direct visual observations of chromosomal structures to determine the steps of gene amplification and the mechanisms by which methotrexate is resistant.
methotrexate is one of the earliest chemotherapy drugs and is still widely used.
researchers sequenced the entire genome of cancer cells that produce resistance, revealing that chromosomal fragmentation initiates ecDNA formation that carries genes that give resistance to cancer treatment.
they also determined how chromosomal fragmentation drives ecDNA formation after gene amplification inside the chromosome.
Shoshani said, "Chromosomal fragmentation converts chromosomal amplification (internal) into extrachromosomal (external) amplification, and ecDNA after gene amplification can be re-integrated into chromosomal positions to cope with DNA damage caused by chemotherapy or radiotherapy."
new study highlights the role of chromosomal fragmentation at all critical stages of the DNA life cycle in which the cancer cells amplification occur, explaining how cancer cells become more invasive or resistant.
" Cleveland said, "We identified recurring DNA fragmentation as a driver of anti-cancer drug resistance and the DNA repair pathways necessary to reassemble fragments of shredded chromosomes, which allowed for the rational design of combination drug therapies to prevent cancer patients from developing resistance and thus improve their therapeutic effectiveness."
" Reference: 1.Ofer Shoshani et al. Chromothripsis drives the evolution of gene amplification in cancer. Nature, 2020, doi:10.1038/s41586-020-03064-z. 2.How shattered chromosomes make cancer cells drug-resistant。