1. Department of Medical Oncology,
2. Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science,
3. Department of Pediatric Oncology Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
4. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
5. Division of Hematology, Children's Hospital, Boston, Massachusetts 02115, USA
6. Agilent Technologies, Palo Alto, California 94304, USA
7. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
8. Department of Pathology,
9. Department of Dermatology,
10. Department of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
11. Royal Free and University College Medical School, London NW3 2PF, UK
12. University College London Hospitals, London NW1 2BU, UK
13. Rambam Medical Center and Technion, Haifa 31096, Israel
14. These authors contributed equally to this work.

Correspondence to: Ronald A. DePinho^1,2,10 Correspondence and requests for materials should be addressed to R.A.D. (Email: ron_depinho@dfci.harvard.edu).

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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