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Nat Commun. 2018 Jan 2;9(1):20. doi: 10.1038/s41467-017-02391-6.

Perturbation-response genes reveal signaling footprints in cancer gene expression.

Author information

1
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK.
2
Institute of Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
3
IRI Life Sciences and Institute for Theoretical Biology, Humboldt University Berlin, Philippstr. 13/Haus 18, 10115, Berlin, Germany.
4
Max Delbrück Center for Molecular Medicine (MDC), Berlin Institute for Medical Systems Biology/Berlin Institute of Health, Robert-Rössle-Str. 10, 13092, Berlin, Germany.
5
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SA, UK.
6
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK. saezrodriguez@gmail.com.
7
RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine, Aachen, 52057, Germany. saezrodriguez@gmail.com.

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.

PMID:
29295995
PMCID:
PMC5750219
DOI:
10.1038/s41467-017-02391-6
[Indexed for MEDLINE]
Free PMC Article

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