Characterisation of MicroRNAs in Ulcerative Colitis and Colitis Associated Cancer for Use as Potential Biomarkers

Introduction: Patients with Ulcerative Colitis (UC) are at increased risk of developing Colorectal Cancer termed Colitis Associated Cancer (CAC). They are monitored via a colonoscopy based screening programme. This is resource intensive, invasive, potentially harmful and can miss dysplastic precursor lesions. Accurate biomarkers are therefore required for surveillance purposes in order to prompt early surgical intervention. MicroRNAs (miRNAS) are short non-coding RNAs responsible for regulating genes at a post-transcriptional level that have shown the ability to act as diagnostic biomarkers. Aim: Conduct a feasibility study to profile microRNAs in the colonic mucosa and plasma of patients with Ulcerative Colitis and identify aberrantly expressed miRNAs related to disease progression. Methods: A retrospective cohort of patients with CAC was first characterised to ensure suitability for sequential biomarker discovery from archived colonic mucosal samples. High throughput miRNA microarray profiling was employed as a screening tool to identify differentially expressed miRNAs in a discovery cohort. MiRNAs of interest were subsequently validated using RT-qPCR in an independent cohort. The experiments were repeated using two cohorts of plasma samples collected prospectively from patients undergoing colonoscopic surveillance. Results: Within the colonic mucosa the expression of miR-21 and miR-135b was significantly increased in both dysplastic and CAC tissues when compared to normal and chronic UC tissue. MiR-18a and miR-31 appear to distinguish the CAC cases from normal. MiR-375 expression was significantly up-regulated in the circulation of patients with CAC. Colonic tissue and plasma profiles were found to differ. Conclusion: There is differential expression of miRNAs in both the colonic mucosa and plasma of patients with UC when compared to CAC, Combining different miRNAs increased their ability to differentiate between the disease states. MiRNAs show biomarker potential, and future potential screening blood test will likely be based on a panel of miRNAs. Further validation in larger cohorts is required.