Pan-cancer analysis of transcriptional metabolic dysregulation using The Cancer Genome Atlas

Understanding the levels of metabolic dysregulation in different disease settings is vital for the safe and effective incorporation of metabolism-targeted therapeutics in the clinic. Using transcriptomic data from 10,704 tumor and normal samples from The Cancer Genome Atlas, across 26 disease sites, we developed a novel bioinformatics pipeline that distinguishes tumor from normal tissues, based on differential gene expression for 114 metabolic pathways. This pathway dysregulation was confirmed in separate patient populations, further demonstrating the robustness of this approach. A bootstrapping simulation was then applied to assess whether these alterations were biologically meaningful, rather than expected by chance. We provide distinct examples of the types of analysis that can be accomplished with this tool to understand cancer specific metabolic dysregulation, highlighting novel pathways of interest in both common and rare disease sites. Utilizing a pathway mapping approach to understand patterns of metabolic flux, differential drug sensitivity, can accurately be predicted. Further, the identification of Master Metabolic Transcriptional Regulators, whose expression was highly correlated with pathway gene expression, explains why metabolic differences exist in different disease sites. We demonstrate these also have the ability to segregate patient populations and predict responders to different metabolism-targeted therapeutics.