PT  - JOURNAL ARTICLE
AU  - Anna S. Trigos
AU  - Richard B. Pearson
AU  - Anthony T. Papenfuss
AU  - David L. Goode
TI  - Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer
AID  - 10.1101/388363
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 388363
4099  - http://biorxiv.org/content/early/2018/08/09/388363.short
4100  - http://biorxiv.org/content/early/2018/08/09/388363.full
AB  - 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.