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Chromothripsis in cancer

Nature Reviews Cancer volume 25, pages 79–92 (2025)Cite this article

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Abstract

Chromothripsis is a mutational phenomenon in which a single catastrophic event generates extensive rearrangements of one or a few chromosomes. This extreme form of genome instability has been detected in 30–50% of cancers. Studies conducted in the past few years have uncovered insights into how chromothripsis arises and deciphered some of the cellular and molecular consequences of chromosome shattering. This Review discusses the defining features of chromothripsis and describes its prevalence across different cancer types as indicated by the manifestations of chromothripsis detected in human cancer samples. The different mechanistic models of chromothripsis, derived from in vitro systems that enable causal inference through experimental manipulation, are discussed in detail. The contribution of chromothripsis to cancer development, the selective advantages that cancer cells might gain from chromothripsis, the evolutionary trajectories of chromothriptic tumours, and the potential vulnerabilities and therapeutic opportunities presented by chromothriptic cells are also highlighted.

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Fig. 1: Chromothripsis involves chromosomal shattering and reassembly.
Fig. 2: Prevalence of chromothripsis across adult and paediatric cancer types.
Fig. 3: Mechanistic models of chromothripsis due to DNA damage.
Fig. 4: The links between extrachromosomal DNA and chromothripsis in cancer.
Fig. 5: Timing of chromothripsis in cancer evolutionary trajectories.

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Acknowledgements

The authors thank M. Chan for sharing the circos plot for illustration purposes, and S. Fröhling and the team of the MASTER/DKTK/NCT trial for sharing the data shown in Fig. 1.

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Authors and Affiliations

  1. Group Genome Instability in Tumors, German Cancer Research Center, Heidelberg, Germany

    Milena Simovic-Lorenz & Aurélie Ernst

  2. German Cancer Consortium (DKTK), Heidelberg, Germany

    Milena Simovic-Lorenz & Aurélie Ernst

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  1. Milena Simovic-Lorenz
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  2. Aurélie Ernst
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The authors contributed equally to all aspects of the article.

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Correspondence to Aurélie Ernst.

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Glossary

Chromosome bridges

Abnormal nuclear structure that arises from end-to-end chromosome fusions after DNA breakage or telomere crisis, incomplete DNA replication, or failed resolution of chromosome catenation.

dN/dS ratio

The rate of synonymous substitutions, assumed to be neutral, compared with the rate of non-synonymous substitutions, which result in amino acid changes and can be acted on by selection pressure.

Kataegis

A hypermutation phenomenon that has been identified in multiple cancer genomes and characterized by localized clusters of single base pair substitutions.

Kinetochore

During eukaryotic cell division, the attachment of spindle fibres to this disc-shaped protein structure enables the sister chromatids to be pulled apart.

Micronuclei

Aberrant nuclear structures that form around lagging mitotic chromosomes or chromosomal fragments that lack centromeres.

Robertsonian translocation

A constitutional centric-fusion chromosomal translocation in which the two long arms of acrocentric chromosomes (13, 14, 15, 21 or 22) fuse at or close to their centromeres to form a single chromosome (which can segregate normally at cell division if one of the two centromeres is inactivated).

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Simovic-Lorenz, M., Ernst, A. Chromothripsis in cancer. Nat Rev Cancer 25, 79–92 (2025). https://doi.org/10.1038/s41568-024-00769-5

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