• A Corrigendum to this article was published on 03 July 2013

Abstract

Cancer chromosomal instability (CIN) results in an increased rate of change of chromosome number and structure and generates intratumour heterogeneity1,2. CIN is observed in most solid tumours and is associated with both poor prognosis and drug resistance3,4. Understanding a mechanistic basis for CIN is therefore paramount. Here we find evidence for impaired replication fork progression and increased DNA replication stress in CIN+ colorectal cancer (CRC) cells relative to CIN CRC cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. We identify three new CIN-suppressor genes (PIGN (also known as MCD4), MEX3C (RKHD2) and ZNF516 (KIAA0222)) encoded on chromosome 18q that are subject to frequent copy number loss in CIN+ CRC. Chromosome 18q loss was temporally associated with aneuploidy onset at the adenoma–carcinoma transition. CIN-suppressor gene silencing leads to DNA replication stress, structural chromosome abnormalities and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication-associated damage5, reduces the frequency of chromosome segregation errors after CIN-suppressor gene silencing, and attenuates segregation errors and DNA damage in CIN+ cells. These data implicate a central role for replication stress in the generation of structural and numerical CIN, which may inform new therapeutic approaches to limit intratumour heterogeneity.

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Acknowledgements

We thank A. Straube for reagents. C.S. is a senior Medical Research Council clinical research fellow and is funded by Cancer Research UK, the Medical Research Council, EU FP7 (projects PREDICT and RESPONSIFY), Prostate Cancer Foundation, and the Breast Cancer Research Foundation. We thank A. Futreal and The Wellcome Trust Sanger Centre and The Cancer Genome Atlas Research Network for providing genomics data. I.P.T. is supported by the Oxford Biomedical Research Centre and Cancer Research UK. J.B. is funded by the Danish Cancer Society, the Lundbeck Foundation, and the European Commission (FP7 projects DDResponse, Biomedreg and Infla-Care). T.H. is funded by the Swedish Cancer Society, the Swedish Research Council and the Torsten and Ragnar Söderberg Foundation.

Author information

Author notes

    • Rebecca A. Burrell
    •  & Sarah E. McClelland

    These authors contributed equally to this work.

Affiliations

  1. Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK

    • Rebecca A. Burrell
    • , Sarah E. McClelland
    • , David Endesfelder
    • , Nadeem Shaikh
    • , Nnennaya Kanu
    • , Sally M. Dewhurst
    • , Eva Gronroos
    • , Su Kit Chew
    • , Andrew J. Rowan
    • , Michael Howell
    • , Axel Behrens
    •  & Charles Swanton
  2. University of Applied Sciences Koblenz, RheinAhrCampus, Department of Mathematics and Technology, Joseph-Rovan-Allee 2, 53424 Remagen, Germany

    • David Endesfelder
    • , Arne Schenk
    •  & Maik Kschischo
  3. Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Box 1031, Stockholm S-171 21, Sweden

    • Petra Groth
    • , Marie-Christine Weller
    •  & Thomas Helleday
  4. Molecular and Population Genetics and NIHR Biomedical Research Centre, The Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK

    • Enric Domingo
    •  & Ian P. Tomlinson
  5. UCL Cancer Institute, Paul O’Gorman Building, Huntley Street, London WC1E 6BT, UK

    • Su Kit Chew
    •  & Charles Swanton
  6. Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel

    • Michal Sheffer
  7. Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark

    • Jiri Bartek
  8. Institute of Molecular and Translational Medicine, Palacky University Olomouc, CZ-775 15, Czech Republic

    • Jiri Bartek

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Contributions

C.S., R.A.B., S.E.M., J.B. and T.H. devised experiments. R.A.B. and S.E.M. performed most cell biological experiments with help from N.S., S.K.C., E.G., S.M.D., A.J.R. and N.K. D.E., A.S. and M.S. performed bioinformatics analysis supervised by M.K. P.G., M.-C.W. and T.H. performed and analysed the DNA fibre assays. E.D. and I.P.T. provided the adenoma-in-carcinoma cohort and CGH for aneuploid tumours. M.H. and A.B. provided experimental advice. C.S. supervised all aspects of the project. C.S., R.A.B., S.E.M., I.P.T. and J.B. wrote the paper. All authors discussed results and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Charles Swanton.

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DOI

https://doi.org/10.1038/nature11935

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