title: Epigenetic regulation of WNT signaling pathway genes in inflammatory bowel disease (IBD) associated neoplasia.
abstract: BACKGROUND
  WNT signaling pathway dysregulation is an important event in the pathogenesis of colorectal cancer (CRC) with APC mutations seen in more than 80% of sporadic CRC. However, such mutations in the WNT signaling pathway genes are rare in inflammatory bowel disease (IBD) associated neoplasia (dysplasia and cancer). This study examined the role of epigenetic silencing of WNT signaling pathway genes in the pathogenesis of IBD-associated neoplasia.
  
  
  METHODS
  Paraffin-embedded tissue samples were obtained and methylation of ten WNT signaling pathway genes, including APC1A, APC2, SFRP1, SFRP2, SFRP4, SFRP5, DKK1, DKK3, WIF1 and LKB1, was analyzed. Methylation analysis was performed on 41 IBD samples, 27 normal colon samples (NCs), and 24 sporadic CRC samples.
  
  
  RESULTS
  Methylation of WNT signaling pathway genes is a frequent and early event in IBD and IBD-associated neoplasia. A progressive increase in the percentage of methylated genes in the WNT signaling pathway from NCs (4.2%) to IBD colitis (39.7%) to IBD-associated neoplasia (63.4%) was seen (NCs vs. IBD colitis, p < 0.01; IBD colitis vs. IBD-associated neoplasia, p = 0.01). In the univariate logistic regression model, methylation of APC2 (OR 4.7, 95% CI: 1.1-20.63, p = 0.04), SFRP1 (OR 5.1, 95% CI: 1.1-31.9, p = 0.04), and SFRP2 (OR 5.1, 95% CI: 1.1-32.3, p = 0.04) was associated with progression from IBD colitis to IBD-associated neoplasia, while APC1A methylation was borderline significant (OR 4.1, 95% CI: 0.95-17.5, p = 0.06). In the multivariate logistic regression model, methylation of APC1A and APC2 was more likely to be associated with IBD-associated neoplasia than IBD colitis. (OR APC1A: 6.4, 95% CI: 1.1-37.7 p = 0.04; OR APC2 9.1, 95% CI: 1.3-61.7, p = 0.02).
  
  
  CONCLUSIONS
  Methylation of the WNT signaling genes is an early event seen in patients with IBD colitis and there is a progressive increase in methylation of the WNT signaling genes during development of IBD-associated neoplasia. Moreover, methylation of APC1A, APC2, SFRP1, and SFRP2 appears to mark progression from IBD colitis to IBD-associated neoplasia, and these genes may serve as biomarkers for IBD-associated neoplasia.
authors: Department of Surgery, Johns Hopkins University, Baltimore, MD 21231, USA.
authors: Mashaal
authors: M
authors: Dhir
authors: Elizabeth A
authors: EA
authors: Montgomery
authors: Sabine C
authors: SC
authors: Glöckner
authors: Kornel E
authors: KE
authors: Schuebel
authors: Craig M
authors: CM
authors: Hooker
authors: James G
authors: JG
authors: Herman
authors: Stephen B
authors: SB
authors: Baylin
authors: Susan L
authors: SL
authors: Gearhart
authors: Nita
authors: N
authors: Ahuja
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051153:Wnt Proteins