Chromothripsis Promotes Cancer Cell Growth

A new study by researchers at the University of California describes how chromothripsis breaks up chromosomes, which then rearrange in ways that ultimately promote cancer cell growth. Their findings were published in Nature. 

"These rearrangements can occur in a single step," said first author Ofer Shoshani. "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.'"

The team 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. Then, they 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 into extrachromosomal amplifications and that amplified ecDNA can then reintegrate into chromosomal locations in response to DNA damage from chemotherapy or radiotherapy," said Shoshani. "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."