Review Article | Published:

Chromothripsis and cancer: causes and consequences of chromosome shattering

Nature Reviews Cancer volume 12, pages 663670 (2012) | Download Citation


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.

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

  2. 2.

    , & The impact of translocations and gene fusions on cancer causation. Nature Rev. Cancer 7, 233–245 (2007).

  3. 3.

    et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011). First report defining the phenomenon of chromothripsis and its implications for cancer development.

  4. 4.

    & DNA double-strand break repair pathways, chromosomal rearrangements and cancer. Semin. Cell Dev. Biol. 22, 886–897 (2011).

  5. 5.

    & Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 25, 409–433 (2011).

  6. 6.

    & The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204 (2010).

  7. 7.

    & Pathways of mammalian replication fork restart. Nature Rev. Mol. Cell Biol. 11, 683–687 (2010).

  8. 8.

    et al. Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Mol. Cell 39, 25–35 (2010).

  9. 9.

    et al. Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science 329, 219–223 (2010).

  10. 10.

    & The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).

  11. 11.

    , & An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).

  12. 12.

    , , & Mechanisms for recurrent and complex human genomic rearrangements. Curr. Opin. Genet. Dev. 22, 211–220 (2012).

  13. 13.

    , & Complex human chromosomal and genomic rearrangements. Trends Genet. 25, 298–307 (2009).

  14. 14.

    et al. Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer. Genome Biol. 12, R103 (2011).

  15. 15.

    , , & Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood 118, 675–678 (2011).

  16. 16.

    et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483, 589–593 (2012).

  17. 17.

    et al. Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms. Cell Rep. 1, 648–655 (2012).

  18. 18.

    et al. Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nature Genet. 44, 390–397 (2012).

  19. 19.

    et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146, 889–903 (2011). This report finds evidence of chromothripsis in non-cancer cells and proposes that it occurs through replication-mediated mechanisms of repair.

  20. 20.

    et al. Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Hum. Mol. Genet. 20, 1916–1924 (2011).

  21. 21.

    , & DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007).

  22. 22.

    , & A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 5, e1000327 (2009).

  23. 23.

    & Chromothripsis and human disease: piecing together the shattering process. Cell 148, 29–32 (2012).

  24. 24.

    & Cancer: When catastrophe strikes a cell. Nature 470, 476–477 (2011).

  25. 25.

    , , & The consequences of structural genomic alterations in humans: genomic disorders, genomic instability and cancer. Semin. Cell Dev. Biol. 22, 875–885 (2011).

  26. 26.

    & Cancer genomes evolve by pulverizing single chromosomes. Cell 144, 9–10 (2011).

  27. 27.

    Merotelic kinetochore orientation, aneuploidy, and cancer. Biochim. Biophys. Acta 1786, 32–40 (2008).

  28. 28.

    et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482, 53–58 (2012). This report provides a plausible model to explain how chromothripsis can occur in chromosomes contained within micronuclei.

  29. 29.

    , & DNA damage signaling in response to double-strand breaks during mitosis. J. Cell Biol. 190, 197–207 (2010).

  30. 30.

    et al. A Mitotic Phosphorylation Feedback Network Connects Cdk1, Plk1, 53BP1, and Chk2 to Inactivate the G2/M DNA Damage Checkpoint. PLoS Biol. 8, e1000287 (2010).

  31. 31.

    & Mammalian cell fusion: induction of premature chromosome condensation in interphase nuclei. Nature 226, 717–722 (1970).

  32. 32.

    et al. Lagging chromosomes entrapped in micronuclei are not 'lost' by cells. Cell Res. 22, 932–935 (2012).

  33. 33.

    et al. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148, 908–921 (2012).

  34. 34.

    et al. Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. Mutagenesis 26, 125–132 (2011).

  35. 35.

    , , , & Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333, 1895–1898 (2011).

  36. 36.

    et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043–1047 (2005).

  37. 37.

    , , & Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 16, 475–486 (2009).

  38. 38.

    & Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J. Cell Biol. 188, 369–381 (2010).

  39. 39.

    et al. The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis. Proc. Natl Acad. Sci. USA 107, 14188–14193 (2010).

  40. 40.

    et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148, 59–71 (2012). This report shows that cells containing mutated versions of p53 are more prone to suffer chromothriptic events, an outcome that can be predicted from the micronucleus model for generating chromothripsis.

  41. 41.

    et al. Functional genomic screens identify CINP as a genome maintenance protein. Proc. Natl Acad. Sci. USA 106, 19304–19309 (2009).

  42. 42.

    & Evidence for chromosome instability in vivo in Bloom syndrome: increased numbers of micronuclei in exfoliated cells. Hum. Genet. 71, 187–191 (1985).

  43. 43.

    , , & Sensitivity to five mutagens in Fanconi's anemia as measured by the micronucleus method. Cancer Res. 38, 2983–2988 (1978).

  44. 44.

    & The DNA damage response and cancer therapy. Nature 481, 287–294 (2012).

  45. 45.

    et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012).

  46. 46.

    & Template switching: from replication fork repair to genome rearrangements. Cell 131, 1228–1239 (2007).

Download references


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.

Author information

Author notes

    • Josep V. Forment
    •  & Abderrahmane Kaidi

    These authors contributed equally to this work.


  1. The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.

    • Josep V. Forment
    • , Abderrahmane Kaidi
    •  & Stephen P. Jackson


  1. Search for Josep V. Forment in:

  2. Search for Abderrahmane Kaidi in:

  3. Search for Stephen P. Jackson in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Stephen P. Jackson.


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.

About this article

Publication history



Further reading