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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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

    • Richard S. Maser
    • , Bhudipa Choudhury
    • , Peter J. Campbell
    •  & Bin Feng

    These authors contributed equally to this work.

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

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Competing interests

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

Corresponding author

Correspondence to Ronald A. DePinho.

Supplementary information

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    Supplementary Information

    This file contains Supplementary Figures S1-S6 and Supplementary Tables S1-S7 with Legends.

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