Gatto Francesco, Schulze Almut, Nielsen Jens
Department of Biology and Biological Engineering, Chalmers University of Technology, 41296 Göteborg, Sweden.
Theodor-Boveri-Institute, Biocenter, 97074 Würzburg, Germany; Comprehensive Cancer Center Mainfranken, 97080 Würzburg, Germany.
Cell Rep. 2016 Jul 19;16(3):878-95. doi: 10.1016/j.celrep.2016.06.038. Epub 2016 Jul 7.
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.
突变是大多数癌症克隆进化的基础。然而，目前仍缺乏对癌症中突变是否因导致特定生物过程失调（而与癌症类型无关）而被选择的系统分析。在本研究中，我们关联了1082个肿瘤的基因组和转录组。我们发现九个常见的突变基因与基因表达的显著变化相关，这些变化主要集中在代谢方面。进一步的网络分析将这种集中限定在一个反应网络中，称为AraX，它涉及花生四烯酸和外源性物质的谷胱甘肽和氧介导的代谢。在一个由4462个样本组成的独立队列中，所有九个突变基因均与AraX的失调持续相关。在所有代谢途径中，AraX失调是患者生存的最强预测指标。这些发现表明致癌突变驱动了一个选择过程，该过程集中于AraX网络的失调。
