1. Cancer Biology
  2. Computational and Systems Biology
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Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer

  1. Anna S Trigos
  2. Richard B Pearson
  3. Anthony T Papenfuss
  4. David L Goode  Is a corresponding author
  1. Peter MacCallum Cancer Centre, Australia
  2. The University of Melbourne, Australia
Research Article
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Cite this article as: eLife 2019;8:e40947 doi: 10.7554/eLife.40947

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.

Article and author information

Author details

  1. Anna S Trigos

    Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Richard B Pearson

    Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Anthony T Papenfuss

    Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. David L Goode

    Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
    For correspondence
    david.goode@petermac.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3277-6562

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.

Reviewing Editor

  1. Alfonso Valencia, Barcelona Supercomputing Center - BSC, Spain

Publication history

  1. Received: August 9, 2018
  2. Accepted: February 6, 2019
  3. Accepted Manuscript published: February 26, 2019 (version 1)
  4. Version of Record published: March 6, 2019 (version 2)

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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