title: Discovering functional modules by identifying recurrent and mutually exclusive mutational patterns in tumors.
abstract: BACKGROUND
  Assays of multiple tumor samples frequently reveal recurrent genomic aberrations, including point mutations and copy-number alterations, that affect individual genes. Analyses that extend beyond single genes are often restricted to examining pathways, interactions and functional modules that are already known.
  
  
  METHODS
  We present a method that identifies functional modules without any information other than patterns of recurrent and mutually exclusive aberrations (RME patterns) that arise due to positive selection for key cancer phenotypes. Our algorithm efficiently constructs and searches networks of potential interactions and identifies significant modules (RME modules) by using the algorithmic significance test.
  
  
  RESULTS
  We apply the method to the TCGA collection of 145 glioblastoma samples, resulting in extension of known pathways and discovery of new functional modules. The method predicts a role for EP300 that was previously unknown in glioblastoma. We demonstrate the clinical relevance of these results by validating that expression of EP300 is prognostic, predicting survival independent of age at diagnosis and tumor grade.
  
  
  CONCLUSIONS
  We have developed a sensitive, simple, and fast method for automatically detecting functional modules in tumors based solely on patterns of recurrent genomic aberration. Due to its ability to analyze very large amounts of diverse data, we expect it to be increasingly useful when applied to the many tumor panels scheduled to be assayed in the near future.
authors.affiliation: Graduate Program in Structural and Computational Biology and Molecular Biophysics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Settle
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Milosavljevic
mesh_terms: D003198:Computer Simulation; D050881:E1A-Associated p300 Protein / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis
chemical_list: D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human