Methylated miR-124, -137, and -34b/c as predictive biomarkers for ulcerative colitis-associated colorectal neoplasia.

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e14631 Background: Accumulating evidence suggests that microRNAs (miRNAs) can be targets of methylation-induced silencing in colorectal cancer, which can occur in an age-dependent manner, and constitutes an epigenetic “field defect”. We hypothesized whether methylation of miR-124, -137 and -34b/c can predict colorectal neoplasia in patients with ulcerative colitis (UC). Methods: We examined 185 samples from 70 UC patients (45 patients without neoplasia, 12 with dysplasia and 13 with cancers) for the methylation status of miR-124, -137 and -34b/c by quantitative bisulfite pyrosequencing analysis. In addition, expression levels of these 3 miRNAs in dysplastic (n=12), cancerous (n=13) and non-neoplastic UC mucosa (n=20) were quantified by TaqMan qRT-PCR. Results: MiR-124 and -137 methylation levels were significantly higher in rectal tissues than in proximal mucosa from non-neoplastic UC tissues, and were significantly associated with age and disease duration in rectal tissues. Methylation levels of all 3 miRNAs were significantly higher in dysplasia and cancer compared to mucosa without neoplasia, and showed a “field defect” in the non-neoplastic rectal tissues from patients with cancer . Receiver operating characteristic (ROC) analysis revealed that methylation levels of all 3 miRNAs in non-neoplastic rectal tissues could discriminate patients with cancer from those without (miR-124 AUC value = 0.74; miR-137 AUC = 0.79; miR-34b/c AUC=0.72). Furthermore, methylated miR-137 in non-neoplastic rectal tissues allowed discrimination of UC patients with neoplasia from those without (AUC = 0.76), and independently predicted neoplasia (OR= 5.55; 95% CI: 1.40–22.05; P = 0.0148). Expression levels of all 3 miRNAs were significantly downregulated in dysplasia or cancer compared to non-neoplastic UC mucosa, and the expression and methylation were negatively correlated. Conclusions: Methylation of miR-124, -137 and -34b/c in rectal biopsies, particularly miR-137, may serve as novel predictive biomarkers for neoplasia in UC patients. Restoration of expression by reversing their methylation status could be an attractive strategy to slow or reverse age-related UC-associated neoplasia.