Chromothripsis Generates Oncogene-Containing Extrachromosomal DNA

Amplification of genomic regions containing oncogenic driver genes can promote cancer development and lead to treatment resistance. In addition to being found in their normal genomic locations as intrachromosomal homogeneously staining regions (HSR), amplified oncogenes can be observed on extrachromosomal DNA such as double minute (DM) chromosomes, which are small, circular, paired chromatin bodies often found in cancer cells. Shoshani and colleagues found that cervical cancer cells exhibited DHFR amplification in the form of HSRs or DM chromosomes following treatment with the DHFR inhibitor methotrexate, with stronger, more consistent selective pressure being associated with amplifications on DM chromosomes. Control clones that did not develop methotrexate resistance did not have genomic rearrangements absent in parent clones, but resistant clones had showed signs that chromothripsis—the shattering of chromosomes and random religation of the fragments into new chromosomes—was the cause of DM chromosome formation. Additionally, heightened selective pressure induced by increased concentrations of methotrexate promoted further structural evolution of the DM chromosomes, a process also mediated by chromothripsis, leading to the formation of DM chromosomes with higher DHFR copy number. Interestingly, causing random DNA double-strand breaks in the DM chromosome–containing cells led to reintegration of the DM chromosomes near chromosome ends, yielding chromosomes with ectopic HSRs containing amplified DHFR. Subsequent breakage–fusion–bridge cycles, which are initiated by telomere loss and cause chromosome instability, led to the formation of micronuclei containing new DM chromosomes that were observed to undergo additional chromothripsis events. Collectively, these findings implicate chromothripsis as a driver of oncogenic gene amplification that occurs as a result of drug-induced selective pressure.

Shoshani O, Brunner SF, Yaeger R, Ly P, Nechemia-Arbely Y, Kim DH, et al. Chromothripsis drives the evolution of gene amplification in cancer. Nature 2020 Dec 23 [Epub ahead of print].

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