title: Bioinformatics analysis of thousands of TCGA tumors to determine the involvement of epigenetic regulators in human cancer.
abstract: BACKGROUND
  Many cancer cells show distorted epigenetic landscapes. The Cancer Genome Atlas (TCGA) project profiles thousands of tumors, allowing the discovery of somatic alterations in the epigenetic machinery and the identification of potential cancer drivers among members of epigenetic protein families.
  
  
  METHODS
  We integrated mutation, expression, and copy number data from 5943 tumors from 13 cancer types to train a classification model that predicts the likelihood of being an oncogene (OG), tumor suppressor (TSG) or neutral gene (NG). We applied this predictor to epigenetic regulator genes (ERGs), and used differential expression and correlation network analysis to identify dysregulated ERGs along with co-expressed cancer genes. Furthermore, we quantified global proteomic changes by mass spectrometry after EZH2 inhibition.
  
  
  RESULTS
  Mutation-based classifiers uncovered the OG-like profile of DNMT3A and TSG-like profiles for several ERGs. Differential gene expression and correlation network analyses revealed that EZH2 is the most significantly over-expressed ERG in cancer and is co-regulated with a cell cycle network. Proteomic analysis showed that EZH2 inhibition induced down-regulation of cell cycle regulators in lymphoma cells.
  
  
  CONCLUSIONS
  Using classical driver genes to train an OG/TSG predictor, we determined the most predictive features at the gene level. Our predictor uncovered one OG and several TSGs among ERGs. Expression analyses elucidated multiple dysregulated ERGs including EZH2 as member of a co-expressed cell cycle network.
authors.forename: Florian
authors.initials: F
authors.lastname: Gnad
authors.forename: Sophia
authors.initials: S
authors.lastname: Doll
authors.forename: Gerard
authors.initials: G
authors.lastname: Manning
authors.forename: David
authors.initials: D
authors.lastname: Arnott
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D019295:Computational Biology; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D009857:Oncogenes; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D020543:Proteome / Q000235:genetics
chemical_list: D020543:Proteome; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2