Mapping chromothripsis across human cancer cell lines reveals genome evolution and therapeutic vulnerabilities

Authors

Leor, G., Ben-Yishay, T., Tarrab, A., Eliezer, Y., Winkler, T., Goetz, M., Raz, L., Reuveni, E., Shamir, R., Ben-David, U.

Abstract

Chromothripsis is a catastrophic chromosomal rearrangement found in ~40% of primary tumors, yet its landscape in cancer cell lines (CCLs) remains uncharacterized. To address this gap, we developed a pipeline to detect chromothripsis-like events from copy-number data alone, and mapped their occurrence across 1,646 human CCLs. Chromothripsis patterns were broadly conserved between primary tumors and CCLs, but CCLs displayed some distinct features and a significantly higher prevalence of chromothripsis. Chromothripsis continued to emerge during culture propagation, likely contributing to its increased prevalence in CCLs. Integrating genomic and functional data revealed selective vulnerabilities: chromothriptic cells were resistant to DNA damage-inducing agents but highly sensitive to histone deacetylase inhibitors (HDACi). Using isogenic models, we validated that HDACi could synergistically sensitize chromothriptic cells to DNA damage-inducing agents. Our study establishes the first comprehensive resource of chromothripsis in CCLs and reveals functional consequences and therapeutic vulnerabilities of chromothripsis-positive cancers.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 31 Oct 2026.

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