Epigenetic Regulation of WNT Signaling Pathway Genes in Inflammatory Bowel Disease (IBD) Associated Neoplasia
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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.
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.
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).
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.
KeywordsIBD Methylation WNT signaling Colorectal cancer
- 10.Hata K, Watanabe T, Kazama S, Suzuki K, Shinozaki M, Yokoyama T, et al. Earlier surveillance colonoscopy programme improves survival in patients with ulcerative colitis associated colorectal cancer: results of a 23-year surveillance programme in the Japanese population. Br J Cancer 2003;89(7):1232–1236. doi:10.1038/sj.bjc.6601247.PubMedCrossRefGoogle Scholar
- 23.Fleisher AS, Esteller M, Harpaz N, Leytin A, Rashid A, Xu Y, et al. Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer Res 2000;60(17):4864–4868.PubMedGoogle Scholar
- 37.Bafico A, Gazit A, Pramila T, Finch PW, Yaniv A, Aaronson SA. Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J Biol Chem 1999;274(23):16180–16187. doi:10.1074/jbc.274.23.16180.PubMedCrossRefGoogle Scholar
- 42.van Dekken H, Wink JC, Vissers KJ, Franken PF, Ruud Schouten W, Hop WCJ, Kuipers EJ, Fodde R, Janneke van der Woude C. Wnt pathway-related gene expression during malignant progression in ulcerative colitis. Acta Histochem 2007;109(4):266–272. doi:10.1016/j.acthis.2007.02.007.PubMedCrossRefGoogle Scholar
- 71.Levin B, Lieberman DA, McFarland B, Andrews KS, Brooks D, Dash C, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Cancer J Clin 2008;58:130–160.CrossRefGoogle Scholar