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
Citations
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Long-term mitotic DNA damage promotes chromokinesin-mediated missegregation of polar chromosomes in cancer cells
Helder Maiato,Cristina Ferrás +1 more
TL;DR: In this article , the authors show that long-term mitotic DNA damage specifically stabilizes kinetochore-microtubule attachments in cancer cells, causing the missegregation of polar chromosomes due to the action of arm-ejection forces by chromokinesins.
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EccBase: A high-quality database for exploration and characterization of extrachromosomal circular DNAs in cancer
Haiyang Sun,Lingyun Zou +1 more
TL;DR: EccBase as mentioned in this paper is the first database for eccDNA data, which mainly collects eccDNAs from Homo sapiens (n = 754,391) and Mus musculus (n= 481,381).
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Extrachromosomal DNA (ecDNA) in cancer: mechanisms, functions, and clinical implications
TL;DR: Extrachromosomal DNA (ecDNA) is circular DNA that plays an important role in the development and heterogeneity of cancer as mentioned in this paper, and the rapid evolution of methods to detect ecDNA including microscopic and sequencing approaches has greatly enhanced our knowledge of the role of ecDNA in cancer development and evolution.
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Cannabis- and Substance-Related Carcinogenesis in Europe: A Lagged Causal Inferential Panel Regression Study
TL;DR: In this paper, the authors investigated the relationship between high-dose cannabis use and reproductive problems and potential genetic impacts, concluding that it is a more important carcinogen than tobacco and alcohol and fulfills epidemiological qualitative and quantitative criteria for causality for 25/41 cancers.
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TL;DR: It is found that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis, which has important implications for the origins of genomic remodeling and temporal emergence of cancer.
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