Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer

Abstract
Data availability
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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.

The following previously published data sets were used

1. The Cancer Genome Atlas
(2018) The Cancer Genome Atlas RNAseq V2 gene expression data
Publicly available from database website.

https://portal.gdc.cancer.gov/
1. The Cancer Genome Atlas
(2018) The Cancer Genome Atlas Point Mutation data generated with Muse, Mutec, SomaticSniper, Varscan
Publicly available from database website.

https://portal.gdc.cancer.gov/
(2017) Pathway Commons Network database
Publicly available from database website.

https://www.pathwaycommons.org/
1. Project Achilles
(2018) avana_public_18Q1
Publicly available from database website.

https://portals.broadinstitute.org/achilles/datasets/all
1. Cancer Cell Line Encyclopedia
(2018) CCLE_DepMap_18Q1_maf_20180207
Publicly available from database website.

https://portals.broadinstitute.org/ccle/data
1. Cancer Cell Line Encyclopedia
(2013) CCLE_copynumber_byGene_2013-12-03
Publicly available from database website.

https://portals.broadinstitute.org/ccle/data
1. Genomics of Drug Sensitivity in Cancer
(2016) v17_fitted_dose_response
Publicly available from database website.

https://www.cancerrxgene.org/downloads / ftp://ftp.sanger.ac.uk/pub4/cancerrxgene/releases/release-6.0/
1. The Cancer Genome Atlas
(2018) The Cancer Genome Atlas CNV data
Publicly available from database website.

https://portal.gdc.cancer.gov/
(2018) Revolver (lung and breast cancer)
Publicly available from GitHub.

https://github.com/caravagn/revolver
1. Broad Institute
(2018) MSigDB
Publicly available from database.

http://software.broadinstitute.org/gsea/msigdb/genesets.jsp?collection=CP:KEGG

Article and author information

Author details

Anna S Trigos

Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
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.
Anthony T Papenfuss

Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
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.

"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.

Copyright

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.