title: CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer.
abstract: BACKGROUND
  The CpG island methylator phenotype (CIMP), characterised by widespread promoter methylation, is associated with microsatellite instability (MSI) and BRAF mutation in colorectal cancer. The independent effect of CIMP, MSI and BRAF mutation on prognosis remains uncertain.
  
  
  METHODS
  Utilising 649 colon cancers (stage I-IV) in two independent cohort studies, we quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) as well as CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN by using MethyLight technology. We examined MSI, KRAS and BRAF status. Cox proportional hazard models computed hazard ratios (HRs) for colon cancer-specific and overall mortalities, adjusting for patient characteristics and tumoral molecular features.
  
  
  RESULTS
  After adjustment for other predictors of patient survival, patients with CIMP-high cancers (126 (19%) tumours with >or=6/8 methylated CIMP-specific promoters) experienced a significantly low colon cancer-specific mortality (multivariate HR 0.44, 95% confidence interval (CI) 0.22 to 0.88), whereas the BRAF mutation was significantly associated with a high cancer-specific mortality (multivariate HR 1.97, 95% CI 1.13 to 3.42). A trend toward a low cancer-specific mortality was observed for MSI-high tumours (multivariate HR 0.70, 95% CI 0.36 to 1.37). In stratified analyses, CIMP-high tumours were associated with a significant reduction in colon cancer-specific mortality, regardless of both MSI and BRAF status. The relation between CIMP-high and lower mortality appeared to be consistent across all stages. KRAS mutation was unrelated to prognostic significance.
  
  
  CONCLUSIONS
  CIMP-high appears to be an independent predictor of a low colon cancer-specific mortality, while BRAF mutation is associated with a high colon cancer-specific mortality.
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA. shuji_ogino@dfci.harvard.edu
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kirkner
authors.forename: Takako
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000368:Aged; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D004812:Epidemiologic Methods; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D014481:United States / Q000453:epidemiology
chemical_list: D004273:DNA, Neoplasm; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf