A DNA methylation test on routine biopsy samples could flag which ulcerative colitis patients are developing pre-cancerous changes years before standard histology detects them. People with long-standing ulcerative colitis face a sharply elevated risk of colorectal cancer, so they undergo regular surveillance colonoscopies. Yet current pathology misses many early neoplasias, and patients with negative results can still develop cancer before their next scope. The problem is not a lack of surveillance but a lack of sensitivity in the test itself. The researchers will first optimise methylation biomarkers on stored tissue samples, then build a high-throughput sequencing pipeline, and finally run a multicentre test-accuracy study. If the methylation test reliably identifies patients who need a follow-up colonoscopy within months, clinicians could catch dangerous lesions earlier and spare low-risk patients from unnecessary procedures. If the test performs well, it could become a standard adjunct to histology in colitis surveillance programmes, shifting practice from interval-based screening to risk-stratified, biologically guided follow-up. That would reduce both missed cancers and over-surveillance, quietly improving a diagnostic pathway that currently leaves too many patients in the gap between scopes.
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To determine whether methylation analysis of surveillance biopsies taken from ulcerative colitis patients can improve the early detection of neoplastic change, this project is organised in 3 modules: 1: Optimisation of methylation biomarkers in a retrospective study of bowel mucosal samples collected from 160 cases (harbouring colorectal neoplasms and 320 controls (low risk colitis patients) from three hospitals. 2: Technology Development within BUMP, evaluating a high-throughput next generation bisulphite sequencing approach, delivering a robust analytical pipeline. 3: A prospective, multicentre test accuracy cohort study Study Population: Chronic ulcerative colitis of over 10 years with disease beyond the splenic flexure, in protocolised surveillance program. Index and reference test: Mucosal biopsies taken for histology, subjected to a supplementary DNA methylation test. Methylation positive patients will undergo a further colonoscopy (reference test) at 4- 6 months, as well as a random sample of twice as many methylation test negative patients. Primary outcome: The occurrence of dysplasia in mucosal biopsies taken at follow up colonoscopy at 4-6 months in patients demonstrating hypermethylation (the positive predictive value). Sample size: Undertaking the tests in a cohort of 1000 will provide over 90% power to prove that the positive predictive value is over 15% with a 5% significance level, and have over 90% power to show the diagnostic odds ratio is significantly (P<0.05) different from one. . Statistical analysis: Analysis for the primary outcome will estimate positive and negative predictive values of methylation as the proportion of those methylation positive at the initial colonoscopy who are detected with CAN at the reference colonoscopy, and the proportion methylation negative who are free of CAN at the reference colonoscopy, respectively. Milestones: Module 1: collation of FFPE samples (– 6 months). Validation of b) our markers (- 9 months), published markers ( – 18 months). Failure to show acceptable performance of markers - No-Go decision. Module 2: assay development 15 months, protocolisation of the analysis– 18 months. Failure to develop a robust assay will prompt reverting to existing pyrosequencing assay. Module 3: will be, IRAS approval across all sites-15 months, recruitment months 18 - 26, IDMC review at months 24 and 30.
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