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Chromothripsis drives DNA amplification in cancer cells developing drug resistance

ABSTRACT: Gene amplification leading to increased oncogene expression or anticancer drug resistance is a frequent event in cancer. Cytogenetic, genomic, and transcriptomic analyses were used to determine the initiating events of gene amplification in a tunable cell culture system developing resistance to chemotherapy. Chromosome shattering (chromothripsis) was found to be a major resistance driver through the production of extra-chromosomal double minutes either directly or subsequent to formation of a homogenous staining region (HSR). Formation and maintenance of double minutes were enhanced by PARP and DNA-PK activities. Double minutes were found to be highly dynamic, undergoing structural evolution to produce increased drug tolerance or re-integration into ectopic chromosomes under conditions of DNA damage. Genome rearrangement profiles produced through acquired drug resistance are similar to human cancer examples with oncogene amplification. Thus, chromothripsis is a driver of genome evolution that enables rapid acquisition of tolerance to altered growth conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE119979 | GEO | 2020/09/14

REPOSITORIES: GEO

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Chromothripsis drives DNA amplification in cancer cells developing drug resistance

Project description:Gene amplification leading to increased oncogene expression or anticancer drug resistance is a frequent event in cancer. Cytogenetic, genomic, and transcriptomic analyses were used to determine the initiating events of gene amplification in a tunable cell culture system developing resistance to chemotherapy. Chromosome shattering (chromothripsis) was found to be a major resistance driver through the production of extra-chromosomal double minutes either directly or subsequent to formation of a homogenous staining region (HSR). Formation and maintenance of double minutes were enhanced by PARP and DNA-PK activities. Double minutes were found to be highly dynamic, undergoing structural evolution to produce increased drug tolerance or re-integration into ectopic chromosomes under conditions of DNA damage. Genome rearrangement profiles produced through acquired drug resistance are similar to human cancer examples with oncogene amplification. Thus, chromothripsis is a driver of genome evolution that enables rapid acquisition of tolerance to altered growth conditions.

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Chromothripsis drives DNA amplification in cancer cells developing drug resistance

Project description:Chromothripsis drives DNA amplification in cancer cells developing drug resistance

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