title: Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients.
abstract: BACKGROUND
  In colorectal cancer (CRC), tumour microsatellite instability (MSI) status and CpG island methylator phenotype (CIMP) status are indicators of patient outcome, but the molecular events that give rise to these outcomes remain largely unknown. Wnt5a is a critical regulator of non-canonical Wnt activity and promoter hypermethylation of this gene has emerging prognostic roles in CRC; however the frequency and prognostic significance of this epigenetic event have not been explored in the context of colorectal tumour subtype. Consequently, we investigated the frequency and prognostic significance of Wnt5a methylation in a large cohort of MSI-stratified CRCs.
  
  
  METHODS
  Methylation was quantified in a large cohort of 1232 colorectal carcinomas from two clinically distinct populations from Canada. Associations were examined between methylation status and clinicopathlogical features, including tumour MSI status, BRAF V600E mutation, and patient survival.
  
  
  RESULTS
  In Ontario, Wnt5a methylation was strongly associated with MSI tumours after adjustment for age, sex, and tumour location (odds ratio (OR)=4.2, 95% confidence interval (CI)=2.4-7.4, P<10(-6)) and with BRAF V600E mutation, a marker of CIMP (OR=12.3, 95% CI=6.9-21.7, P<10(-17)), but was not associated with patient survival. Concordant results were obtained in Newfoundland.
  
  
  CONCLUSIONS
  Methylation of Wnt5a is associated with distinct tumour subtypes, strengthening the evidence of an epigenetic-mediated Wnt bias in CRC.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5S 1A1.
authors.forename: J B
authors.initials: JB
authors.lastname: Rawson
authors.forename: M
authors.initials: M
authors.lastname: Mrkonjic
authors.forename: D
authors.initials: D
authors.lastname: Daftary
authors.forename: E
authors.initials: E
authors.lastname: Dicks
authors.forename: D D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: H B
authors.initials: HB
authors.lastname: Younghusband
authors.forename: P S
authors.initials: PS
authors.lastname: Parfrey
authors.forename: J P
authors.initials: JP
authors.lastname: Young
authors.forename: A
authors.initials: A
authors.lastname: Pollett
authors.forename: R C
authors.initials: RC
authors.lastname: Green
authors.forename: S
authors.initials: S
authors.lastname: Gallinger
authors.forename: J R
authors.initials: JR
authors.lastname: McLaughlin
authors.forename: J A
authors.initials: JA
authors.lastname: Knight
authors.forename: B
authors.initials: B
authors.lastname: Bapat
mesh_terms: D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051153:Wnt Proteins / Q000235:genetics*; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf