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Epigenetic Regulation of WNT Signaling Pathway Genes in Inflammatory Bowel Disease (Ibd) Neoplasia
Mashaal Dhir*1, Elizabeth a. Montgomery2, Kornel Schuebel3, Susan L. Gearhart1, Nita Ahuja1,3
1Surgery, Johns Hopkins University, Baltimore, MD; 2Pathology, Johns Hopkins University, Baltimore, MD; 3Oncology, Johns Hopkins University, Baltimore, MD
Background: DNA methylation of promoter CpG islands in the Wnt signaling pathway is an important event in the pathogenesis of Colorectal Cancer (CRC). We hypothesized that chronic inflammatory states, like IBD, may lead to increased aberrant methylation and inactivation of Wnt genes which in turn accelerate the development of cancer. This study examined the role of epigenetic silencing of Wnt genes in the pathogenesis of IBD Neoplasia (Dysplasia and Cancer).
Methods: Paraffin embedded tissue samples were obtained from The Johns Hopkins Hospital Pathology archive with IRB approval. We analyzed 11 Wnt genes using methylation specific PCR including APC1A, APC2, dickkopf family genes (DKK1, DKK2), soluble frizzled related proteins (sFRP1, sFRP2, sFRP4, sFRP5), Wnt inhibitory factor-1 (WIF-1), Delta like3 (DLL3) and a serine threonine kinase, LKB1. Methylation analysis was performed in 41 IBD samples [6 IBD cancers, 2 High grade dysplasia (HGD), 8 Low grade dysplasias (LGD) and 25 IBD colitis] from 20 IBD patients (Median disease duration=12 years), 27 normal colons (NCs) and 24 sporadic CRCs (Stage 1-3).
Results: There was no significant difference in the overall frequency of methylation of Wnt signaling pathway genes in sporadic CRC and IBD cancers (52% vs. 61%; p=0.42). However, a progressive increase in the percentage of methylated genes from NCs (3.7%) to IBD Colitis (39.7%) to IBD Neoplasia (63.39%) was seen (NC vs. IBD Colitis p<0.001, IBD Colitis vs. IBD associated Neoplasia p=0.016). More importantly, a distinct increase in methylation of APC1A and APC2 was seen during progression to IBD Neoplasia (Figure 1). Multivariate logistic regression analysis showed that methylation of APC1a and APC2 were predictive of IBD Neoplasia as compared to IBD colitis (OR APC1a:6.2, 95% CI: 1.1-36.3; OR APC2:8.5, 95% CI: 1.2-59.0).
Conclusions: The frequency of methylation of the Wnt signaling pathway genes increases progressively during development of IBD Neoplasia. Moreover, the findings of early methylation of APC1A and APC2 in IBD associated dysplasia may provide a method for early detection of IBD associated carcinoma.
Figure1: Progressive increase in methylation frequency of APC1A & APC2 during IBD Neoplasia
