Graph-theoretical model of global human interactome reveals enhanced long-range communicability in cancer networks

<div><p>Malignant transformation is known to involve substantial rearrangement of the molecular genetic landscape of the cell. A common approach to analysis of these alterations is a reductionist one and consists of finding a compact set of differentially expressed genes or associated signaling pathways. However, due to intrinsic tumor heterogeneity and tissue specificity, biomarkers defined by a small number of genes/pathways exhibit substantial variability. As an alternative to compact differential signatures, global features of genetic cell machinery are conceivable. Global network descriptors suggested in previous works are, however, known to potentially be biased by overrepresentation of interactions between frequently studied genes-proteins. Here, we construct a cellular network of 74538 directional and differential gene expression weighted protein-protein and gene regulatory interactions, and perform graph-theoretical analysis of global human interactome using a novel, degree-independent feature—the normalized total communicability (NTC). We apply this framework to assess differences in total information flow between different cancer (BRCA/COAD/GBM) and non-cancer interactomes. Our experimental results reveal that different cancer interactomes are characterized by significant enhancement of long-range NTC, which arises from circulation of information flow within robustly organized gene subnetworks. Although enhancement of NTC emerges in different cancer types from different genomic profiles, we identified a subset of 90 common genes that are related to elevated NTC in all studied tumors. Our ontological analysis shows that these genes are associated with enhanced cell division, DNA replication, stress response, and other cellular functions and processes typically upregulated in cancer. We conclude that enhancement of long-range NTC manifested in the correlated activity of genes whose tight coordination is required for survival and proliferation of all tumor cells, and, thus, can be seen as a graph-theoretical equivalent to some hallmarks of cancer. The computational framework for differential network analysis presented herein is of potential interest for a wide range of network perturbation problems given by single or multiple gene-protein activation-inhibition.</p>