Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer
- Peter MacCallum Cancer Centre, Australia
- The University of Melbourne, Australia
Abstract
Extensive transcriptional alterations are observed in cancer, many of which activate core biological processes established in unicellular organisms or suppress differentiation pathways formed in metazoans. Through rigorous, integrative analysis of genomics data from a range of solid tumours, we show many transcriptional changes in tumours are tied to mutations disrupting regulatory interactions between unicellular and multicellular genes within human gene regulatory networks (GRNs). Recurrent point mutations were enriched in regulator genes linking unicellular and multicellular subnetworks, while copy-number alterations affected downstream target genes in distinctly unicellular and multicellular regions of the GRN. Our results depict drivers of tumourigenesis as genes that created key regulatory links during the evolution of early multicellular life, whose dysfunction creates widespread dysregulation of primitive elements of the GRN. Several genes we identified as important in this process were associated with drug response, demonstrating the potential clinical value of our approach.
Data availability
All data used during this study was obtained from the public databases indicated in the manuscript.Results generated during this study are included as supporting files.
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The Cancer Genome Atlas RNAseq V2 gene expression dataPublicly available from database website.
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The Cancer Genome Atlas Point Mutation data generated with Muse, Mutec, SomaticSniper, VarscanPublicly available from database website.
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Pathway Commons Network databasePublicly available from database website.
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avana_public_18Q1Publicly available from database website.
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CCLE_DepMap_18Q1_maf_20180207Publicly available from database website.
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CCLE_copynumber_byGene_2013-12-03Publicly available from database website.
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v17_fitted_dose_responsePublicly available from database website.
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The Cancer Genome Atlas CNV dataPublicly available from database website.
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Revolver (lung and breast cancer)Publicly available from GitHub.
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MSigDBPublicly available from database.
Article and author information
Author details
Funding
University of Melbourne
- Anna S Trigos
National Health and Medical Research Council
- Richard B Pearson
- Anthony T Papenfuss
- David L Goode
The Peter MacCallum Cancer Centre Foundation
- David L Goode
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Trigos et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer
eLife 8:e40947.
https://doi.org/10.7554/eLife.40947
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