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⇱ Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers | Nature

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Abstract

Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the neoplastic transformation process. Here we engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Along with targeted re-sequencing, our comparative oncogenomic studies identified FBXW7 and PTEN to be commonly deleted both in murine lymphomas and in human T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL). The murine cancers acquire widespread recurrent amplifications and deletions targeting loci syntenic to those not only in human T-ALL but also in diverse human haematopoietic, mesenchymal and epithelial tumours. These results indicate that murine and human tumours experience common biological processes driven by orthologous genetic events in their malignant evolution. The highly concordant nature of genomic events encourages the use of genomically unstable murine cancer models in the discovery of biological driver events in the human oncogenome.

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Figure 1: The TKO model.
Figure 2: FBXW7 alterations are common in human T-ALL and conserved in the murine TKO tumours.
Figure 3: Conservation of PTEN genetic alterations in human and mouse T-ALLs.
Figure 4: Substantial overlap between genomic alterations of murine TKO lymphomas and human tumours of diverse origins.

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Acknowledgements

We thank Y. Zhang, A. Yu and K. Marmon for excellent mouse husbandry and care, and C. Greenman and E. Pleasance for helpful discussion on statistical analyses. R.S.M. was supported by the Damon Runyon Cancer Research Foundation. P.J.C. was supported by the Kay Kendall Leukaemia Fund, and B.C. is supported by a grant from GlaxoSmithKline. K.K.W. was supported by an NIH award. M.R.S. and P.A.F. are supported by the Wellcome Trust. L.C. and R.A.D. are supported by NIH grants, LeBow Fund to Cure Myeloma, the Chris Elliot Foundation, and the Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science. R.A.D. is an Ellison Foundation for Medical Research Senior Scholar and an American Cancer Society Research Professor.

Author Contributions R.S.M., B.C., P.J.C. and B.F. performed the experiments and contributed equally as first authors. M.R.S., L.C., P.A.F. and R.A.D. supervised experiments and contributed equally as senior authors. R.S.M. and R.A.D. generated and characterized the instability mouse model. B.F. and L.C. conducted the oncogenomic analyses. B.C., P.J.C., M.R.S. and P.A.F. provided the re-sequencing analyses. A.P., J.O., A.G., E.I., I.P., E.L., V.M., S.J., K.M., S.Z., S.E., C.S., G.H., C.B., E.S.M., R.W., O.K., C.N., M.M. and V.D. performed experiments. A.G., L.F., A.K.F., A.H.G., J.M.R. and A.T.L. contributed patient samples and clinical data. K.K.W., J.A. and A.T.L. coordinated experiments. Y.A.W. contributed to the writing of the manuscript.

All microarray data are available at the Gene Expression Array Omnibus website (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE7615.

Author information

Author notes

  1. Richard S. Maser, Bhudipa Choudhury, Peter J. Campbell and Bin Feng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology,,

    Richard S. Maser, Kwok-Kin Wong, Vidya Mani, Shan Jiang, Kate McNamara, Sara Zaghlul, Eric S. Martin, Ruprecht Wiedemeyer, Omar Kabbarah, Cristina Nogueira, Yaoqi A. Wang, Lynda Chin & Ronald A. DePinho

  2. Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science,,

    Bin Feng, Alexei Protopopov, Elena Ivanova, Ilana Perna, Yaoqi A. Wang, Lynda Chin & Ronald A. DePinho

  3. Department of Pediatric Oncology Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA,

    Jennifer O’Neil, Alejandro Gutierrez & A. Thomas Look

  4. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK,

    Bhudipa Choudhury, Peter J. Campbell, Sarah Edkins, Claire Stevens, Michael R. Stratton & P. Andrew Futreal

  5. Division of Hematology, Children’s Hospital, Boston, Massachusetts 02115, USA,

    Alejandro Gutierrez

  6. Agilent Technologies, Palo Alto, California 94304, USA,

    Eric Lin

  7. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA,

    Cameron Brennan

  8. Department of Pathology,,

    Gavin Histen & Jon Aster

  9. Department of Dermatology,,

    Lynda Chin

  10. Department of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Ronald A. DePinho

  11. Royal Free and University College Medical School, London NW3 2PF, UK,

    Marc Mansour, Veronique Duke, Letizia Foroni & Adele K. Fielding

  12. University College London Hospitals, London NW1 2BU, UK,

    Anthony H. Goldstone

  13. Rambam Medical Center and Technion, Haifa 31096, Israel,

    Jacob M. Rowe

Authors
  1. Richard S. Maser
  2. Bhudipa Choudhury
  3. Peter J. Campbell
  4. Bin Feng
  5. Kwok-Kin Wong
  6. Alexei Protopopov
  7. Jennifer O’Neil
  8. Alejandro Gutierrez
  9. Elena Ivanova
  10. Ilana Perna
  11. Eric Lin
  12. Vidya Mani
  13. Shan Jiang
  14. Kate McNamara
  15. Sara Zaghlul
  16. Sarah Edkins
  17. Claire Stevens
  18. Cameron Brennan
  19. Eric S. Martin
  20. Ruprecht Wiedemeyer
  21. Omar Kabbarah
  22. Cristina Nogueira
  23. Gavin Histen
  24. Jon Aster
  25. Marc Mansour
  26. Veronique Duke
  27. Letizia Foroni
  28. Adele K. Fielding
  29. Anthony H. Goldstone
  30. Jacob M. Rowe
  31. Yaoqi A. Wang
  32. A. Thomas Look
  33. Michael R. Stratton
  34. Lynda Chin
  35. P. Andrew Futreal
  36. Ronald A. DePinho

Corresponding author

Correspondence to Ronald A. DePinho.

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Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

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Maser, R., Choudhury, B., Campbell, P. et al. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 447, 966–971 (2007). https://doi.org/10.1038/nature05886

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