Chromothripsis drives the evolution of gene amplification in cancer.
Ofer Shoshani,Simon F. Brunner,Rona Yaeger,Peter Ly,Yael Nechemia-Arbely,Dong Hyun Kim,Rongxin Fang,Guillaume A. Castillon,Miao Yu,Julia S. Z. Li,Ying Sun,Mark H. Ellisman,Bing Ren,Peter J. Campbell,Peter J. Campbell,Don W. Cleveland +15 more
TLDR
In this paper, the authors used whole-genome sequencing of clonal cell isolates that developed chemotherapeutic resistance to show that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).Abstract:
Focal chromosomal amplification contributes to the initiation of cancer by mediating overexpression of oncogenes1–3, and to the development of cancer therapy resistance by increasing the expression of genes whose action diminishes the efficacy of anti-cancer drugs. Here we used whole-genome sequencing of clonal cell isolates that developed chemotherapeutic resistance to show that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification (also known as double minutes) through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Longitudinal analyses revealed that a further increase in drug tolerance is achieved by structural evolution of ecDNAs through additional rounds of chromothripsis. In situ Hi-C sequencing showed that ecDNAs preferentially tether near chromosome ends, where they re-integrate when DNA damage is present. Intrachromosomal amplifications that formed initially under low-level drug selection underwent continuing breakage–fusion–bridge cycles, generating amplicons more than 100 megabases in length that became trapped within interphase bridges and then shattered, thereby producing micronuclei whose encapsulated ecDNAs are substrates for chromothripsis. We identified similar genome rearrangement profiles linked to localized gene amplification in human cancers with acquired drug resistance or oncogene amplifications. We propose that chromothripsis is a primary mechanism that accelerates genomic DNA rearrangement and amplification into ecDNA and enables rapid acquisition of tolerance to altered growth conditions. Chromothripsis—a process during which chromosomes are ‘shattered’—drives the evolution of gene amplification and subsequent drug resistance in cancer cells.read more
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References
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Journal Article
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Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition
Rona Yaeger,Zhan Yao,David M. Hyman,Jaclyn F. Hechtman,Efsevia Vakiani,Huiyong Zhao,Wenjing Su,Lu Wang,Andrew Joelson,Andrea Cercek,José Baselga,Elisa de Stanchina,Leonard B. Saltz,Michael F. Berger,David B. Solit,Neal Rosen +15 more
TL;DR: It is shown that mechanisms of resistance converge on formation of RAF dimerization and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer.
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