title: Identification of a poor-prognosis BRAF-mutant-like population of patients with colon cancer.
abstract: OBJECTIVE
  Our purpose was development and assessment of a BRAF-mutant gene expression signature for colon cancer (CC) and the study of its prognostic implications.
  
  
  METHODS
  A set of 668 stage II and III CC samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial were used to assess differential gene expression between c.1799T>A (p.V600E) BRAF mutant and non-BRAF, non-KRAS mutant cancers (double wild type) and to construct a gene expression-based classifier for detecting BRAF mutant samples with high sensitivity. The classifier was validated in independent data sets, and survival rates were compared between classifier positive and negative tumors.
  
  
  RESULTS
  A 64 gene-based classifier was developed with 96% sensitivity and 86% specificity for detecting BRAF mutant tumors in PETACC-3 and independent samples. A subpopulation of BRAF wild-type patients (30% of KRAS mutants, 13% of double wild type) showed a gene expression pattern and had poor overall survival and survival after relapse, similar to those observed in BRAF-mutant patients. Thus they form a distinct prognostic subgroup within their mutation class.
  
  
  CONCLUSIONS
  A characteristic pattern of gene expression is associated with and accurately predicts BRAF mutation status and, in addition, identifies a population of BRAF mutated-like KRAS mutants and double wild-type patients with similarly poor prognosis. This suggests a common biology between these tumors and provides a novel classification tool for cancers, adding prognostic and biologic information that is not captured by the mutation status alone. These results may guide therapeutic strategies for this patient segment and may help in population stratification for clinical trials.
authors.affiliation: Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Quartier Sorge, Genopode, CH-1015 Lausanne, Switzerland. vlad.popovici@isb-sib.ch
authors.forename: Vlad
authors.initials: V
authors.lastname: Popovici
authors.forename: Eva
authors.initials: E
authors.lastname: Budinska
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.forename: Scott
authors.initials: S
authors.lastname: Weinrich
authors.forename: Heather
authors.initials: H
authors.lastname: Estrella
authors.forename: Graeme
authors.initials: G
authors.lastname: Hodgson
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.forename: Fred T
authors.initials: FT
authors.lastname: Bosman
authors.forename: Arnaud D
authors.initials: AD
authors.lastname: Roth
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D015203:Reproducibility of Results; D018570:Risk Assessment; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins