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, and large numbers of somatic genomic alterations, associated with a predisposition to cancer2. However, it remains difficult to distinguish background, or ‘passenger’, cancer mutations from causal, or ‘driver’, mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations3. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining 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, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer.
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Acknowledgements
We thank members of the Center for Cancer Systems Biology (CCSB) and J. Aster, M. Meyerson, W. Kaelin, G. Superti-Furga and S. Sunyaev for discussions, and J.W. Harper, W. Hahn, P. Howley, Y. Jacob, M. Imperiale, I. Koralnik, H. Pfister and D. Wang for reagents. This work was primarily supported by Center of Excellence in Genomic Science (CEGS) grant P50HG004233 from the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) awarded to M.V. (principal investigator), A.-L.B., J.A.D., E.K., J.A.M., K.M., J.Q. and F.P.R. Additional funding included Institute Sponsored Research funds from the Dana-Farber Cancer Institute Strategic Initiative to M.V.; NIH grants R01HG001715 to M.V., D.E.H. and F.P.R.; R01CA093804, R01CA063113 and P01CA050661 to J.A.D.; R01CA081135, R01CA066980 and U01CA141583 to K.M.; R01CA131354, R01CA047006 and R01CA085180 to E.K.; T32HL007208 and K08HL098361 to R.C.D.; K08CA122833 to R.B.; F32GM095284 and K25HG006031 to M.P.; Canada Excellence Research Chairs (CERC) Program, Canadian Institute for Advanced Research Fellowship and Ontario Research Fund to F.P.R.; and James S. McDonnell Foundation grant 220020084 to A.-L.B. M.V. is a ‘Chercheur Qualifié Honoraire’ from the Fonds de la Recherche Scientifique (Wallonia-Brussels Federation, Belgium).
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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. M.A.C., T.R., M.G., A.D., M.A., Ma.T. and S.P. contributed equally and should be considered joint second authors; D.E.H., K.M., J.A.M., J.Q., F.P.R., J.A.D. and M.V should be considered joint senior authors; additional co-authors are listed alphabetically.
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Rozenblatt-Rosen, O., Deo, R., Padi, M. et al. Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 487, 491–495 (2012). https://doi.org/10.1038/nature11288
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DOI: https://doi.org/10.1038/nature11288
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