title: Systematic Analysis Reveals that Cancer Mutations Converge on Deregulated Metabolism of Arachidonate and Xenobiotics.
abstract: Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network.
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, 41296 Göteborg, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gatto
authors.affiliation: Theodor-Boveri-Institute, Biocenter, 97074 Würzburg, Germany; Comprehensive Cancer Center Mainfranken, 97080 Würzburg, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Schulze
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, 41296 Göteborg, Sweden. Electronic address: nielsenj@chalmers.se.
authors.forename: Jens
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism*; D060965:Clonal Evolution / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D015262:Xenobiotics; D016718:Arachidonic Acid