Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
Richard B Pearson
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
Anthony T Papenfuss
Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia; Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, Australia
Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
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 tumors, we show many transcriptional changes in tumors 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.
