title: Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas.
abstract: BACKGROUND
  Nonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas.
  
  
  METHODS
  Quantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples.
  
  
  RESULTS
  Increased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (p < 0.01). Combining both adenoma types, a positive trend between APC mutation and both WIF-1 and DKK3 methylation was observed (p < 0.05).
  
  
  CONCLUSIONS
  Methylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations.
authors.forename: Quirinus J M
authors.initials: QJ
authors.lastname: Voorham
authors.forename: Jerry
authors.initials: J
authors.lastname: Janssen
authors.forename: Marianne
authors.initials: M
authors.lastname: Tijssen
authors.forename: Suzanne
authors.initials: S
authors.lastname: Snellenberg
authors.forename: Sandra
authors.initials: S
authors.lastname: Mongera
authors.forename: Nicole C T
authors.initials: NC
authors.lastname: van Grieken
authors.forename: Heike
authors.initials: H
authors.lastname: Grabsch
authors.forename: Martin
authors.initials: M
authors.lastname: Kliment
authors.forename: Bjorn J
authors.initials: BJ
authors.lastname: Rembacken
authors.forename: Chris J J
authors.initials: CJ
authors.lastname: Mulder
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.forename: Renske D M
authors.initials: RD
authors.lastname: Steenbergen
authors.affiliation: Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. b.carvalho@vumc.nl.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000236:Adenoma / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D018925:Chemokines; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D011123:Polyploidy; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics; D055760:SOXF Transcription Factors / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012097:Repressor Proteins; D055760:SOXF Transcription Factors; C498624:DKK3 protein, human; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109188:SOX17 protein, human; C485569:WIF1 protein, human