Cancer is one of the world's greatest health afflictions because, unlike some diseases, it is a moving target, constantly evolving to evade and resist treatment.

In a paper published in the journal Nature, researchers describe how a phenomenon known as "chromothripsis" breaks up chromosomes, which then reassemble in ways that ultimately promote cancer cell growth.

Chromothripsis is a catastrophic mutational event in a cell's history that involves massive rearrangement of its genome, as opposed to a gradual acquisition of rearrangements and mutations over time. Genomic rearrangement is a key characteristic of many cancers, allowing mutated cells to grow or grow faster, unaffected by anti-cancer therapies.

"These rearrangements can occur in a single step," said first author. "During chromothripsis, a chromosome in a cell is shattered into many pieces, hundreds in some cases, followed by reassembly in a shuffled order. Some pieces get lost while others persist as extra-chromosomal DNA (ecDNA). Some of these ecDNA elements promote cancer cell growth and form minute-sized chromosomes called 'double minutes.'"

Research published last year found that up to half of all cancer cells in many types of cancers contain ecDNA carrying cancer-promoting genes.

In the latest study, the authors employed direct visualization of chromosome structure to identify the steps in gene amplification and the mechanism underlying resistance to methotrexate, one of the earliest chemotherapy drugs and still widely used.

In collaboration, the team sequenced the entire genomes of cells developing drug resistance, revealing that chromosome shattering jump-starts formation of ecDNA-carrying genes that confer anti-cancer therapy resistance.

The scientists also identified how chromothripsis drives ecDNA formation after gene amplification inside a chromosome.

"Chromothripsis converts intra-chromosomal amplifications (internal) into extra-chromosomal (external) amplifications and that amplified ecDNA can then reintegrate into chromosomal locations in response to DNA damage from chemotherapy or radiotherapy," said the author. "The new work highlights the role of chromothripsis at all critical stages in the life cycle of amplified DNA in cancer cells, explaining how cancer cells can become more aggressive or drug-resistant."

Said co-senior author: "Our identifications of repetitive DNA shattering as a driver of anti-cancer drug resistance and of DNA repair pathways necessary for reassembling the shattered chromosomal pieces has enabled rational design of combination drug therapies to prevent development of drug resistance in cancer patients, thereby improving their outcome."

https://ucsdnews.ucsd.edu/pressrelease/breaking-bad-how-shattered-chromosomes-make-cancer-cells-drug-resistant

https://www.nature.com/articles/s41586-020-03064-z