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Interpreting Cancer Genomes Using Systematic Host Perturbations by Tumour Virus Proteins Interpreting Cancer Genomes Using Systematic Host Perturbations by Tumour Virus Proteins The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Rozenblatt-Rosen, Orit, Rahul C. Deo, Megha Padi, Guillaume Adelmant, Michael A. Calderwood, Thomas Rolland, Miranda Grace, et al. 2012. Interpreting cancer genomes using systematic host perturbations by tumour virus proteins. Nature 487(7408): 491-495. Published Version doi:10.1038/nature11288 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:10612841 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA NIH Public Access Author Manuscript Nature. Author manuscript; available in PMC 2013 January 26. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Nature. 2012 July 26; 487(7408): 491–495. doi:10.1038/nature11288. Interpreting cancer genomes using systematic host perturbations by tumour virus proteins Orit Rozenblatt-Rosen1,2,*,#, Rahul C. Deo3,4,*,#, Megha Padi5,6,*,#, Guillaume Adelmant3,7,*,#, Michael A. Calderwood8,9,10,*,^, Thomas Rolland8,9,*,^, Miranda Grace11,*,^, Amélie Dricot8,9,*,^, Manor Askenazi3,7,*,^, Maria Tavares1,2,7,*,^, Sam Pevzner8,9,12,^, Fieda Abderazzaq5,*, Danielle Byrdsong8,9,*, Anne-Ruxandra Carvunis8,9, Alyce A. Chen11,*, Jingwei Cheng1,2, Mick Correll5, Melissa Duarte8,10,*, Changyu Fan8,9,*, Mariet C. Feltkamp13, Scott B. Ficarro3,7,*, Rachel Franchi8,14,*, Brijesh K. Garg3,7,*, Natali Gulbahce8,15,16,*, Tong Hao8,9,*, Amy M. Holthaus10,*, Robert James8,9,*, Anna Korkhin1,2,*, Larisa Litovchick1,2,*, Jessica C. Mar5,6,*, Theodore R. Pak17, Sabrina Rabello2,8,15,*, Renee Rubio5,*, Yun Shen8,9,*, Saurav Singh3,7, Jennifer M. Spangle11,*, Murat Tasan3,17,*, Shelly Wanamaker8,9,14, James T. Webber3,7, Jennifer Roecklein-Canfield8,14, Eric Johannsen10,*, Albert-László Barabási2,8,15,*, Rameen Beroukhim2,18,19, Elliott Kieff10,*, Michael E. Cusick8,9,*, David E. Hill8,9,*, Karl Münger11,*, Jarrod A. Marto3,7,*, John Quackenbush5,6,*, Frederick P. Roth3,8,17,*, James A. DeCaprio1,2,*, and Marc Vidal8,9,* 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA 2Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA 4Cardiovascular Research Institute, Department of Medicine and Institute for Human Genetics, University of California, San Francisco, California 94143, USA 5Center for Cancer Computational Biology (CCCB), Department of Biostatistics and Computational Biology and Department of Cancer Biology, Dana- Farber Cancer Institute, Boston, Massachusetts 02215, USA 6Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA 7Blais Proteomics Center and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA 8Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA 9Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA 10Infectious Diseases Division, The Channing Laboratory, Brigham and Women’s Hospital and Departments of Medicine and of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA 11Division of Infectious Diseases, Correspondence and request for materials should be addressed to: D.E.H. ([email protected]), K.M. ([email protected]), J.A.M. ([email protected]), J.Q. ([email protected]), F.P.R. ([email protected]), J.A.D. ([email protected]), M.V. ([email protected]).. *Member of the Genomic Variation and Network Perturbation Center of Excellence in Genomic Science, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. #These authors contributed equally to this work and should be considered co-first authors. ^These authors contributed equally to this work and should be considered co-second authors. Additional co-authors are listed alphabetically. Author Contributions O.R.-R., G.A., M.A.C., M.G., A.D., Ma.T., F.A., D.B., A.A.C., J.C., M.C., M.D., M.C.F., S.B.F., R.F., B.K.G., A.M.H., R.J., A.K., L.L., R.R., J.M.S., S.W., J.R.-C. and E.J. performed experiments or contributed new reagents. R.C.D., M.P., G.A., T.R., M.A., S.P., A.-R.C., C.F., N.G., T.H., J.C.M., T.R.P., S.R., Y.S., S.S., Mu.T. and J.T.W. performed computational analysis. O.R.-R., R.C.D., M.P., G.A., M.A.C., T.R., M.E.C., D.E.H., K.M., J.A.M., F.P.R., J.A.D. and M.V. wrote the manuscript. A.-L.B., R.B., E.K., M.E.C., D.E.H., K.M., J.A.M., J.Q., F.P.R., J.A.D. and M.V. designed or advised research. Author Information Microarray data were deposited in the Gene Expression Omnibus database (accession number GSE38467). The authors declare no competing financial interests. Rozenblatt-Rosen et al. Page 2 Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston, NIH-PA Author ManuscriptMassachusetts NIH-PA Author Manuscript 02115, NIH-PA Author Manuscript USA 12Biomedical Engineering Department, Boston University and Boston University School of Medicine, Boston, Massachusetts 02118, USA 13Department of Medical Microbiology, Leiden University Medical center, Leiden, The Netherlands 14Department of Chemistry, Simmons College, Boston, Massachusetts 02115, USA 15Center for Complex Networks Research (CCNR) and Department of Physics, Northeastern University, Boston, Massachusetts 02115, USA 16Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, USA 17Donnelly Centre, University of Toronto and Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, M5G 1X5 Ontario, Canada 18Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA 19The Broad Institute, Cambridge, Massachusetts 02142, USA Abstract Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations1. Genome sequencing efforts have identified numerous germline mutations associated with cancer predisposition and large numbers of somatic genomic alterations2. However, it remains challenging to distinguish between background, or “passenger” and causal, or “driver” cancer mutations in these datasets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations3. To test the hypothesis that genomic variations and tumour viruses may cause cancer via related mechanisms, we systematically examined host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways that go awry in cancer, such as Notch signalling and apoptosis. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches result in increased specificity for cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate prioritization of cancer-causing driver genes so as to advance understanding of the genetic basis of human cancer. Integrative studies of viral proteins have identified host perturbations relevant to viral disease aetiology4,5. We examined whether such a strategy extended systematically across a range of tumour viruses could shed light on cancers even beyond those directly caused by these pathogens. Our hypothesis is inspired by classical examples where DNA tumour virus proteins physically target the products of RB1 or TP53, two well-established germline- inherited and somatically-inactivated tumour-suppressor genes6. We propose that viruses and genomic variations alter local and global properties of cellular networks in similar ways to cause pathological states. Models derived from host perturbations mediated by viral proteins representing the virome7 should serve as surrogates for network perturbations that result from large numbers of genomic variations, or the variome8 (Fig. 1a). We used an integrated pipeline to systematically investigate perturbations of host interactome and transcriptome networks induced by the gene products of four functionally related yet biologically distinct, families of DNA tumour viruses: Human Papillomavirus (HPV), Epstein-Barr Virus (EBV), Adenovirus (Ad5) and Polyomavirus (PyV) (Fig. 1b and Supplementary Table 1 and Supplementary Fig. 1). Nature. Author manuscript; available in PMC 2013 January 26. Rozenblatt-Rosen et al. Page 3 Applying a stringent implementation of the yeast two-hybrid (Y2H) system9, 123 viral
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