Extensive Decoupling of Metabolic Genes in Cancer

Tumorigenesis involves, among other factors, the alteration of metabolic gene expression to support malignant, unrestrained proliferation. Here, we examine how the altered metabolism of cancer cells is reflected in changes in co-expression patterns of metabolic genes between normal and tumor tissues. Our emphasis on changes in the interactions of pairs of genes, rather than on the expression levels of individual genes, exposes changes in the activity of metabolic pathways which do not necessarily show clear patterns of over- or under-expression. 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. Notably, we find that the extent of differential co-expression of a gene is only weakly correlated with its differential expression, suggesting that the two measures probe different features of metabolism. By leveraging our findings against existing pathway knowledge, we extract networks of functionally connected differentially co-expressed genes and the transcription factors which regulate them. Doing so, we identify a previously unreported network of dysregulated metabolic genes in clear cell renal cell carcinoma transcriptionally controlled by the transcription factor HNF4A. While HNF4A shows no significant differential expression, the co-expression HNF4A and several of its regulated target genes in normal tissue is completely abrogated in tumor tissue. Finally, we aggregate the results of differential co-expression 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 located in the mitochondrial electron transport chain, which show significant loss of co-expression in tumor tissue, pointing to potential mitochondrial dysfunction in these tumor types.