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P452. Hypermethylation status in relation to chronic inflammation of inflammatory bowel disease

T. Lobaton Ortega1, D. Azuara2, F. Rodriguez-Moranta1, J. de Oca3, J. Guardiola1, X. San Juan4, D. Montfort5, J. Boadas5, S. Galter5, M. Piqueras6, V. Moreno2, G. Capella2

1Hospital Universitari Bellvitage, Gastroenterology, Barcelona, Spain; 2Institut Catala de Oncologia, Translational Research Laboratory, Barcelona, Spain; 3Hospital Universitari Bellvitge, Surgery, Barcelona, Spain; 4Hospital Universitari Bellvitage, Pathology, Barcelona, Spain; 5Consorci Sanitari Terrasa, Gastroenterology, Barcelona, Spain; 6Consorcio Sanitari Terrasa, Gastroenterology, Barcelona, Spain

Background: Aberrant methylation of tumor suppressor genes is one of the most attractive mechanisms of carcinogenesis in inflammation-related cancer.

Methods: Aim: To investigate the methylation status of genes in normal and inflamed mucosa of IBD. Methods: We analyzedthe tissue preserved in RNA Later from 66 patients with IBD (17 high risk CRC-IBD and 49 low risk CRC-IBD) who underwent colonoscopy. Methylation in stool DNA was also analyzed. Serial colonic biopsies were taken irrespective of the endoscopic disease activity. Biopsy samples were classified as active or inactive disease according to the histological disease activity on the basis of the percentage of neutrophils. Patients with dysplasia or CRC were excluded. We evaluated the methylation status of 3 genes (TGFB2, SLIT2, TMEFF2) using methylation-specific PCR.

Results: A total of112 groups of biopsies from the inflamed (n = 52) and non inflamed (n = 69) mucosa of 66 IBD patients were analyzed. Methylation of TGFB2 was observed in 15/112 (13.4%) samples. Inthe univariate analysis, only the presence of inflammation was associated with methylation (14/15, 93.3% vs. 38/97, 39.2%; p < 0.001). In the multivariate analysis presence of inflammation was an independent risk factor of TGFB2 methylation status (OR 22.3, 95% CI 22.7–176.7, p = 0.004). Methylation of SLIT2 (34/112, 30.6%) was associated with presence of inflammation (26/34, 76.5% vs 26/78, 33.3%; p < 0.001) and extensive IBD (16/34, 47.1% vs 22/78, 28.2%, p = 0.053). In multivariate analysis, the extent of disease, duration of IBD and inflammation were independent risk factors of SLIT2 methylation status (OR: 8.3, 95% CI 3.0–22.6; p < 0.001; OR: 0.95, 95% CI 0.91–0.99, p = 0.047; OR 0.28, 95% CI 0.09–0.79, p = 0.017). TMEFF2aberrant methylation was associated to female sex (8/8, 100% vs, 60/104, 57.7%; p = 0.002) and inflammation (8/8, 100% vs, 44/104, 42%; p = 0.002). No independent risk factors were identified in multivariate analysis.

Conclusions: Colonic inflammation is a risk factor of aberrant genetic methylation. This supports the hypothesis that methylation is a link between inflammation and CCR in IBD.