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.
Cancers arise when harmful changes happen in the genetic information of certain cells. These ‘mutations’ are different from person to person, but overall, they disrupt healthy cells in similar ways. In particular, cancer cells tend to lose features that help cells work together in the body. Researchers have suggested that cancers may emerge when cells stop being able to cooperate with each other as part of an organism.
Our bodies still rely on old genes that were present in our earliest, single-cell ancestors. However, we also have newer genes that evolved when the organisms in our lineage started to have more than one cell. A complex network of signals exists to ensure that both sets of genes work together smoothly, and previous studies have suggested that cancers may appear when this delicate balance is disrupted.
To address this question, Trigos et al. have now used a computational approach to analyse different types of tumours from over 9,000 patients. This showed that, in cancer, many mutations disrupt the genes that coordinate old and new genes. These mutations were usually small, punctual changes in the genetic sequence. However, large modifications, such as an entire gene being deleted or repeated, took place more often in the old or the new genes themselves. Therefore, different classes of mutations have specific roles when disrupting how old and new genes work in cancer.
While certain genes highlighted during this analysis were already known to be associated with cancer, others were not – including genes present during the evolution of the earliest animals on Earth. Looking more closely into how these genes can cause disease may help us better understand and fight cancer.