Perturbation-response genes reveal signaling footprints in cancer gene expression

Michael Schubert, Bertram Klinger, Martina Klünemann, Anja Sieber, Florian Uhlitz, Sascha Sauer, Mathew J. Garnett, Nils Blüthgen and Julio Saez-Rodriguez ()
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Michael Schubert: Wellcome Genome Campus
Bertram Klinger: Charité Universitätsmedizin Berlin
Martina Klünemann: Charité Universitätsmedizin Berlin
Anja Sieber: Charité Universitätsmedizin Berlin
Florian Uhlitz: Charité Universitätsmedizin Berlin
Sascha Sauer: Berlin Institute for Medical Systems Biology/Berlin Institute of Health
Mathew J. Garnett: Wellcome Genome Campus
Nils Blüthgen: Charité Universitätsmedizin Berlin
Julio Saez-Rodriguez: Wellcome Genome Campus

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Aberrant cell signaling can cause cancer and other diseases and is a focal point of drug research. A common approach is to infer signaling activity of pathways from 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 pathway mapping 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 accurately infers pathway activity from gene expression in a wide range of conditions.

Date: 2018
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DOI: 10.1038/s41467-017-02391-6

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