Abstract
Tumorigenesis requires the re-organization of metabolism to support malignant proliferation. We examine how the altered metabolism of cancer cells is reflected in the rewiring of co-expression patterns among metabolic genes. Focusing on breast and clear-cell kidney tumors, we report the existence of key metabolic genes which act as hubs of differential co-expression, showing significantly different co-regulation patterns between normal and tumor states. We compare our findings to those from classical differential expression analysis, and counterintuitively observe that the extent of a gene's differential co-expression only weakly correlates with its differential expression, suggesting that the two measures probe different features of metabolism. Focusing on this discrepancy, we use changes in co-expression patterns to highlight the apparent loss of regulation by the transcription factor HNF4A in clear cell renal cell carcinoma, despite no differential expression of HNF4A. Finally, we aggregate the results of differential co-expression analysis into a Pan-Cancer analysis across seven distinct cancer types to identify pairs of metabolic genes which may be recurrently dysregulated. Among our results is a cluster of four genes, all components of the mitochondrial electron transport chain, which show significant loss of co-expression in tumor tissue, pointing to potential mitochondrial dysfunction in these tumor types.
Highlights
All cellular events, from the transduction of signals to the translation of nucleic acids, rely on the interaction of molecular entities
We examine how the altered metabolism of cancer cells is reflected in the rewiring of co-expression patterns among metabolic genes
Focusing on breast and clear-cell kidney tumors, we report the existence of key metabolic genes which act as hubs of differential coexpression, showing significantly different co-regulation patterns between normal and tumor states
Summary
From the transduction of signals to the translation of nucleic acids, rely on the interaction of molecular entities. One may argue that the fundamental unit of a biological network is not its constituent components (e.g. proteins or genes), but rather the edges representing the interactions between them It follows that the manifestation of disease, of a deranged phenotype of this network, should be evident by observing changes in the wiring and activity of these edges. We study the interactions between pairs of genes encoding metabolic enzymes, and how these interactions change in the course of transformation of normal cells to malignant tumor. This notion of studying “interactions” is important for understanding the network of coupled enzymatic reactions which constitute metabolism. An invigorated field has identified a number of distinct “metabolic lesions” in various tumors, including, for example, the preferential expression of PKM2 [2] and the presence of an oncometabolite, 2-hydroxyglutarate, in cells with activating IDH1 and IDH2 mutations [3]
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