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Perturbation-response genes reveal signaling footprints in cancer gene expression

View ORCID ProfileMichael Schubert, Bertram Klinger, Martina Klünemann, Mathew J Garnett, Nils Blüthgen, View ORCID ProfileJulio Saez-Rodriguez
doi: https://doi.org/10.1101/065672
Michael Schubert
1European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SD, UK
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Bertram Klinger
2 Institute of Pathology, Charité Universitätsmedizin Berlin
3IRI Life Sciences and Institute for Theoretical Biology, Humboldt University Berlin, Germany
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Martina Klünemann
2 Institute of Pathology, Charité Universitätsmedizin Berlin
3IRI Life Sciences and Institute for Theoretical Biology, Humboldt University Berlin, Germany
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Mathew J Garnett
4Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK
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Nils Blüthgen
2 Institute of Pathology, Charité Universitätsmedizin Berlin
3IRI Life Sciences and Institute for Theoretical Biology, Humboldt University Berlin, Germany
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Julio Saez-Rodriguez
1European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SD, UK
5RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine, Aachen 52057, Germany
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  • For correspondence: saezrodriguez@gmail.com
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Abstract

Aberrant cell signaling is known to cause cancer and many other diseases, as well as a focus of treatment. A common approach is to infer its activity on the level of pathways using gene expression. However, mapping gene expression to pathway components disregards the effect of post-translational modifications, and downstream signatures represent very specific experimental conditions. Here we present PROGENy, a method that overcomes both limitations by leveraging a large compendium of publicly available perturbation experiments to yield a common core of Pathway RespOnsive GENes. Unlike existing methods, PROGENy can (i) recover the effect of known driver mutations, (ii) provide or improve strong markers for drug indications, and (iii) distinguish between oncogenic and tumor suppressor pathways for patient survival. Collectively, these results show that PROGENy more accurately infers pathway activity from gene expression than other methods.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 28, 2016.
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Perturbation-response genes reveal signaling footprints in cancer gene expression
Michael Schubert, Bertram Klinger, Martina Klünemann, Mathew J Garnett, Nils Blüthgen, Julio Saez-Rodriguez
bioRxiv 065672; doi: https://doi.org/10.1101/065672
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Perturbation-response genes reveal signaling footprints in cancer gene expression
Michael Schubert, Bertram Klinger, Martina Klünemann, Mathew J Garnett, Nils Blüthgen, Julio Saez-Rodriguez
bioRxiv 065672; doi: https://doi.org/10.1101/065672

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