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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  1. 1.

    & Array comparative genomic hybridization and its applications in cancer. Nature Genet. 37 (Suppl) S11–S17 (2005)

  2. 2.

    et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002)

  3. 3.

    et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004)

  4. 4.

    et al. An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Nature Genet. 37, 48–55 (2005)

  5. 5.

    et al. Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas. Nature Genet. 29, 459–464 (2001)

  6. 6.

    et al. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2, 149–155 (2002)

  7. 7.

    , , & Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis. Oncogene 24, 6597–6604 (2005)

  8. 8.

    et al. Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc. Natl Acad. Sci. USA 103, 5947–5952 (2006)

  9. 9.

    et al. Identification of alterations in DNA copy number in host stromal cells during tumor progression. Proc. Natl Acad. Sci. USA 103, 19848–19853 (2006)

  10. 10.

    et al. Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell 125, 1269–1281 (2006)

  11. 11.

    et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006)

  12. 12.

    et al. Activating Notch1 mutations in mouse models of T-ALL. Blood 107, 781–785 (2005)

  13. 13.

    et al. Comparison of gene expression and DNA copy number changes in a murine model of lung cancer. Genes Chromosom. Cancer 45, 338–348 (2006)

  14. 14.

    et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000)

  15. 15.

    et al. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 109, 811–821 (2002)

  16. 16.

    et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119, 861–872 (2004)

  17. 17.

    et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119, 847–860 (2004)

  18. 18.

    et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005)

  19. 19.

    , , , & Telomere fusion to chromosome breaks reduces oncogenic translocations and tumour formation. Nature Cell Biol. 7, 706–711 (2005)

  20. 20.

    et al. Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis. Cancer Res. 63, 8188–8196 (2003)

  21. 21.

    et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003)

  22. 22.

    & ATM: genome stability, neuronal development, and cancer cross paths. Adv. Cancer Res. 83, 209–254 (2001)

  23. 23.

    et al. Abnormal rearrangement within the α/δ T-cell receptor locus in lymphomas from Atm-deficient mice. Blood 96, 1940–1946 (2000)

  24. 24.

    , , & Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nature Genet. 28, 155–159 (2001)

  25. 25.

    , , , & A central role for chromosome breakage in gene amplification, deletion formation, and amplicon integration. Genes Dev. 5, 160–174 (1991)

  26. 26.

    , , & Notch regulation of lymphocyte development and function. Nature Immunol. 5, 247–253 (2004)

  27. 27.

    et al. TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661 (1991)

  28. 28.

    , & Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393, 382–386 (1998)

  29. 29.

    et al. Array comparative genome hybridization for tumor classification and gene discovery in mouse models of malignant melanoma. Cancer Res. 63, 5352–5356 (2003)

  30. 30.

    et al. Disease-related potential of mutations in transcriptional cofactors CREB-binding protein and p300 in leukemias. Cancer Lett. 213, 11–20 (2004)

  31. 31.

    , & A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell 83, 289–299 (1995)

  32. 32.

    et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nature Genet. 36, 1084–1089 (2004)

  33. 33.

    , , , & Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Cell 112, 243–256 (2003)

  34. 34.

    et al. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature 432, 775–779 (2004)

  35. 35.

    & Mechanisms of tumor suppression by the SCFFbw7. Cell Cycle 4, 1356–1359 (2005)

  36. 36.

    & The biology and clinical relevance of the PTEN tumor suppressor pathway. J. Clin. Oncol. 22, 2954–2963 (2004)

  37. 37.

    et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. 8, 1169–1178 (1998)

  38. 38.

    et al. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res. 64, 4394–4399 (2004)

  39. 39.

    et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 9, 313–325 (2006)

  40. 40.

    et al. High-resolution genomic profiles of human lung cancer. Proc. Natl Acad. Sci. USA 102, 9625–9630 (2005)

  41. 41.

    et al. A census of human cancer genes. Nature Rev. Cancer 4, 177–183 (2004)

  42. 42.

    et al. Inactivation of hCDC4 can cause chromosomal instability. Nature 428, 77–81 (2004)

  43. 43.

    et al. CDC4 mutations occur in a subset of colorectal cancers but are not predicted to cause loss of function and are not associated with chromosomal instability. Cancer Res. 65, 11361–11366 (2005)

  44. 44.

    et al. Infrequent mutations of Archipelago (hAGO, hCDC4, Fbw7) in primary ovarian cancer. Gynecol. Oncol. 98, 124–128 (2005)

  45. 45.

    , & The Notch1/c-Myc Pathway in T cell leukemia. Cell cycle 6, 327–330 (2007)

  46. 46.

    et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999)

  47. 47.

    et al. High-resolution characterization of the pancreatic adenocarcinoma genome. Proc. Natl Acad. Sci. USA 101, 9067–9072 (2004)

  48. 48.

    , , , & High incidence of Notch-1 mutations in adult patients with T-cell acute lymphoblastic leukemia. Leukemia 20, 537–539 (2006)

  49. 49.

    , , & Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557–572 (2004)

  50. 50.

    et al. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 65, 7591–7595 (2005)

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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.


  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.

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