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  • Review Article
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Chromothripsis and cancer: causes and consequences of chromosome shattering

Key Points

  • Chromothripsis is a phenomenon by which tens to thousands of chromosomal rearrangements occur, with the available evidence indicating that chromothripsis can be generated by a single catastrophic event during the life history of a cell.

  • Rearrangements can occur by chromosome shattering and rejoining of pieces by end-joining DNA repair pathways, or by aberrant DNA replication-based mechanisms.

  • Chromothripsis may contribute to cellular transformation, as it occurs early in tumour development: end-joining-based repair can lead to the loss of tumour suppressor functions, oncogenic fusions and oncogene amplification via double-minute chromosomes. In addition, aberrant DNA replication mechanisms taking place during chromothripsis can lead to oncogene amplification.

  • An attractive model for the generation of chromothripsis invokes the involvement of micronuclei. According to this model, chromosomes contained within micronuclei suffer aberrant DNA replication and can then be pulverized in mitosis with subsequent rejoining of DNA segments leading to a derivative chromosome or chromosomes that can be reincorporated into the main nucleus. Chromothripsis is observed with a higher frequency in cells with mutated p53. This leads to a model in which micronuclei formation owing to chromosome segregation errors is allowed in p53-deficient cells, potentially yielding chromothripsis and the evolution of cancer. Defects in chromosome segregation and/or DNA damage response processes may also contribute to carcinogenesis by promoting chromothripsis.

Abstract

Genomic alterations that lead to oncogene activation and tumour suppressor loss are important driving forces for cancer development. Although these changes can accumulate progressively during cancer evolution, recent studies have revealed that many cancer cells harbour chromosomes bearing tens to hundreds of clustered genome rearrangements. In this Review, we describe how this striking phenomenon, termed chromothripsis, is likely to arise through chromosome breakage and inaccurate reassembly. We also discuss the potential diagnostic, prognostic and therapeutic implications of chromothripsis in cancer.

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Figure 1: The DNA damage response to DNA double-strand breaks.
Figure 2: Mechanisms of DNA double-strand break repair.
Figure 3: Mechanisms for generating complex chromosome rearrangements via DNA end-joining pathways.
Figure 4: Mechanisms for generating complex chromosome rearrangements via replicative processes.
Figure 5: A model of chromothripsis and aneuploidy via micronucleus formation.
Figure 6: A timeline of events linking DNA damage response defects, chromothripsis and tumour development.

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Acknowledgements

The authors thank S.P.J. Laboratory members for their advice and support, in particular M. Blasius, R. Belotserkovskaya, K. Dry and J. Travers for critical reviewing and helpful discussions. Research in the S.P.J. Laboratory is supported by grants from Cancer Research UK (C6/A11226), the European Research Council, the European Community's Seventh Framework Program (FP7/2007-2013) grant agreement no. HEALTH-F2-2010-259893 (DDResponse) and by core infrastructure funding from Cancer Research UK (C6946/A14492) and the Wellcome Trust (092096). A.K. is supported by a Herchel Smith Fellowship. S.P.J. receives his salary from the University of Cambridge, supplemented by Cancer Research UK and is an Associate Faculty member of the Wellcome Trust Sanger Institute.

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Correspondence to Stephen P. Jackson.

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Glossary

Collapsed DNA replication forks

Replication forks that have become inactivated through dissociation of the replication machinery and/or generation of a DNA double-strand break. In contrast to a stalled replication fork, which can resume replication once the blockage hindering its progression has been removed, restoration of collapsed replication forks generally requires the use of recombination-based mechanisms. A typical case of replication fork collapse occurs when an active replication fork encounters a single-strand DNA break.

Replicative stress

Abnormal progression of DNA replication that results in hyperactivation of the ATRCHK1 branch of the DNA damage response. If persistent, replicative stress can result in DNA damage. Changes in the timing of activation of DNA replication origins or a shortage of deoxyribonucleotides in S phase are typical causes of replicative stress.

Punctuated equilibrium

A theory that proposes that changes acquired during the evolution of a process occur in rare and rapid events. This contrasts with gradualism theory, which proposes that evolutionary changes are acquired uniformly at a moreorless constant rate.

Copy number states

The number of copies of a chromosome region present in the genome of a cell. In normal diploid cells the copy number state of the whole genome is two. Duplications and deletions are typical examples of gain and loss of copy number, respectively, as is generation of aneuploidy.

Loss of heterozygosity

(LOH). Loss of one of the two alleles of a gene. It is important to distinguish between LOH defined from a genomic perspective (this definition) and LOH defined genetically (loss of normal function of one allele of a gene in which the other allele was already inactivated).

Dicentric chromosome

Product of the fusion between two chromosome regions, each of which contains a centromere. Dicentric chromosomes can be broken in mitosis if the centromeres are pulled towards opposite poles of the dividing cell.

Breakage–fusion–bridge cycles

Chromosomal ends with critically shortened telomeres are highly recombinogenic, and undergo repeated cycles of endtoend fusions, followed by random breakage and then subsequent fusions to generate complex chromosomal rearrangements.

Double-minute chromosomes

Small circular fragments of extra-chromosomal DNA that do not contain telomeres or centromeres but that are maintained in the cell because they confer selective advantages for growth and survival. When observed in cancer cells, they frequently harbour oncogenes.

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Forment, J., Kaidi, A. & Jackson, S. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer 12, 663–670 (2012). https://doi.org/10.1038/nrc3352

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