Mapping chromothripsis across human cancer cell lines reveals genome evolution and therapeutic vulnerabilities
- 1Tel Aviv University
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.
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BibTeX
@misc{leor2026mapping,
title = {{Mapping chromothripsis across human cancer cell lines reveals genome evolution and therapeutic vulnerabilities}},
author = {G. Leor and T. Ben-Yishay and A. Tarrab and Y. Eliezer and T. Winkler and M. Goetz and L. Raz and E. Reuveni and R. Shamir and U. Ben-David},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.763015},
url = {https://www.biorxiv.org/content/10.64898/2026.10.30.763015v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Mapping chromothripsis across human cancer cell lines reveals genome evolution and therapeutic vulnerabilities
AU - G. Leor
AU - T. Ben-Yishay
AU - A. Tarrab
AU - Y. Eliezer
AU - T. Winkler
AU - M. Goetz
AU - L. Raz
AU - E. Reuveni
AU - R. Shamir
AU - U. Ben-David
PY - 2026
DA - 2026/10/30
PB - bioRxiv
DO - 10.64898/2026.10.30.763015
UR - https://www.biorxiv.org/content/10.64898/2026.10.30.763015v1
AB - 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.
ER -