Scientific Abstract
Proposal No. IBD-289R
Principal Investigator: Andrew R. Silver, Ph.D.
Applicant Organization: Queen Mary and Westfield College, University of London (England)
Project Title: MicroRNA expression profiles in blood and tissues in patients with chronic ulcerative colitis: identifying biomarkers for progression to cancer
Period of Award: February 1, 2010 – June 30, 2013
Patients with ulcerative colitis (UC) have an increased risk of developing dysplasia and colorectal cancer (UC-CRC). Therefore, UC patients undergo regular surveillance with a colonoscopy and multiple biopsies. The specificity for histological assessment of biopsies to detect dysplasia is reduced by presence of mucosal inflammation and this reduces the sensitivity of surveillance colonoscopy. Existing serological markers are non-specific and are proxies for generalized inflammation, not markers of disease progression to dysplasia and cancer. Despite appropriate surveillance, some patients will still develop an interval UC-CRC between colonoscopies. Therefore, there is a clear unmet need for reliable biomarkers that will resolve the presence of dysplasia from a background of mucosal inflammation and will predict progression to dysplasia and UC-CRC in UC patients. Biomarkers assayed from blood would further reduce the requirement for regular colonoscopies.
Recent studies support a role for dysregulation of microRNAs (miRNAs) in the initiation and progression of cancer. Consequently, miRNA profiles have distinct potential as markers for cancer diagnosis. MiRNAs negatively regulate mRNA expression through sequence specific interactions and at least one thousand miRNAs are predicted to exist in the human genome, likely regulating almost every cellular process. Importantly, the discovery that stable miRNAs can be detected in serum of patients provides opportunities for minimally invasive patient surveillance using profiles of key miRNAs. We propose that the inflammation-associated changes to the intestinal mucosa that drive progression to dysplasia and UC–CRC result in dysregulated expression of miRNAs, which may be used as biomarkers. MiRNA profiles will be incorporated into a laboratory assay suitable for diagnostic and prognostic use allowing discrimination between abnormal and healthy tissue. We will undertake a multi-centre study to establish miRNA profiles in UC patients across the spectrum of inflammatory disease (inflammation, dysplasia, dysplastic associated lesions / masses - DALMS - and UC-CRCs). It is also possible that some miRNAs circulating in the blood may have potential as distinguishing markers, but are not identified from tissues directly. To ensure that these miRNAs are identified at the earliest stage of this project, we will conduct full miRNA profile analysis of blood samples from UC-patients with dysplasia or cancer. Identifiable profiles, selected using mucosal tissue or blood samples will then be further investigated in circulating serum of additional affected patients. This exploratory project will test a novel idea and direction in terms of surveillance of UC patients and the results will be the basis of a project grant to assess the clinical and health economic benefit of the use of peripheral blood miRNA patterns as a surveillance strategy to prevent UC-CRC. Our ultimate goal is to identify biomarkers of disease progression in UC patients with the potential additional benefit of identifying novel targets for therapeutics, and suitable miRNA profiles for monitoring drug treatment.
Recent studies support a role for dysregulation of microRNAs (miRNAs) in the initiation and progression of cancer. Consequently, miRNA profiles have distinct potential as markers for cancer diagnosis. MiRNAs negatively regulate mRNA expression through sequence specific interactions and at least one thousand miRNAs are predicted to exist in the human genome, likely regulating almost every cellular process. Importantly, the discovery that stable miRNAs can be detected in serum of patients provides opportunities for minimally invasive patient surveillance using profiles of key miRNAs. We propose that the inflammation-associated changes to the intestinal mucosa that drive progression to dysplasia and UC–CRC result in dysregulated expression of miRNAs, which may be used as biomarkers. MiRNA profiles will be incorporated into a laboratory assay suitable for diagnostic and prognostic use allowing discrimination between abnormal and healthy tissue. We will undertake a multi-centre study to establish miRNA profiles in UC patients across the spectrum of inflammatory disease (inflammation, dysplasia, dysplastic associated lesions / masses - DALMS - and UC-CRCs). It is also possible that some miRNAs circulating in the blood may have potential as distinguishing markers, but are not identified from tissues directly. To ensure that these miRNAs are identified at the earliest stage of this project, we will conduct full miRNA profile analysis of blood samples from UC-patients with dysplasia or cancer. Identifiable profiles, selected using mucosal tissue or blood samples will then be further investigated in circulating serum of additional affected patients. This exploratory project will test a novel idea and direction in terms of surveillance of UC patients and the results will be the basis of a project grant to assess the clinical and health economic benefit of the use of peripheral blood miRNA patterns as a surveillance strategy to prevent UC-CRC. Our ultimate goal is to identify biomarkers of disease progression in UC patients with the potential additional benefit of identifying novel targets for therapeutics, and suitable miRNA profiles for monitoring drug treatment.