title: PARADIGM-SHIFT predicts the function of mutations in multiple cancers using pathway impact analysis.
abstract: BACKGROUND
  A current challenge in understanding cancer processes is to pinpoint which mutations influence the onset and progression of disease. Toward this goal, we describe a method called PARADIGM-SHIFT that can predict whether a mutational event is neutral, gain-or loss-of-function in a tumor sample. The method uses a belief-propagation algorithm to infer gene activity from gene expression and copy number data in the context of a set of pathway interactions.
  
  
  RESULTS
  The method was found to be both sensitive and specific on a set of positive and negative controls for multiple cancers for which pathway information was available. Application to the Cancer Genome Atlas glioblastoma, ovarian and lung squamous cancer datasets revealed several novel mutations with predicted high impact including several genes mutated at low frequency suggesting the approach will be complementary to current approaches that rely on the prevalence of events to reach statistical significance.
  
  
  BACKGROUND
  All source code is available at the github repository http:github.org/paradigmshift.
  
  
  BACKGROUND
  jstuart@soe.ucsc.edu
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Biomolecular Engineering and CBSE, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Ng
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.forename: Artem
authors.initials: A
authors.lastname: Sokolov
authors.forename: Theodore
authors.initials: T
authors.lastname: Goldstein
authors.forename: Abel
authors.initials: A
authors.lastname: Gonzalez-Perez
authors.forename: Nuria
authors.initials: N
authors.lastname: Lopez-Bigas
authors.forename: Christopher
authors.initials: C
authors.lastname: Benz
authors.forename: David
authors.initials: D
authors.lastname: Haussler
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Stuart
mesh_terms: D000465:Algorithms; D015870:Gene Expression; D052138:Genes, Neoplasm; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics
chemical_list: D051267:NF-E2-Related Factor 2; D016160:Retinoblastoma Protein