Perturbation-response genes reveal signaling footprints in cancer gene expression

By Michael Schubert, Bertram Klinger, Martina Klünemann, Anja Sieber, F. Uhlitz, Sascha Sauer, Mathew Garnett, Nils Blüthgen, J. Sáez-Rodríguez. Nature Communications, 2016

858 citations recorded by the source corpus.

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. Deregulation of signalling is responsible for many cancer phenotypes. Leveraging available perturbation data, here the authors assess large-scale pathway activity patterns based on consensus downstream readout genes, enabling accurate prediction of the effects of mutations and small molecules.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8f56b30b0104bda99414000178d89e3718ed7ca4

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1. Andrea Pierleoni
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Citations in the corpus

• Best practices for single-cell analysis across modalities (2023, neutral): “3).”
• Open Targets Platform: new developments and updates two years on (2018, methodology): “New data sources for target-disease associations We have incorporated four new data sources to enhance our evidence: Genomics England PanelApp and the PheWAS catalogue (within the data type Genetic associations) and SLAPenrich and PROGENy (for the data type Affected pathways).”