Title: Derek Butler Fellowship: Investigating the clonal origins and dysplasia risk in Barrett's oesophagus
Funder: CORE

Abstract: In very broad terms what is the problem that this project is going to address?There has been a large increase in the number of patients with cancer of the gullet in the UK over the last few decades. The major risk factor is a precancerous disease called Barrett’s oesophagus which is characterised by a microscopic change in the lining of the gullet from a normal simple cell layer to one that is thought to resemble the more complex organisation of the intestine. Barrett’s is common and cancer risk is low, but the large number of patients means cancer is a significant concern and as such patients are routinely examined. This is expensive and is not making a significant impact on the number of overall gullet cancer cases. We therefore need to understand how Barrett’s lesions form and evaluate when they are most likely to develop cancer.We believe that Barrett’s does not in fact resemble the intestine but rather the stomach. Evidence from our laboratory demonstrates this and we hypothesise that Barrett’s originates from the stomach. Work comparing stem cells and the cells they produce in Barrett’s with those of the stomach will reveal their relationship. We will use novel technologies to read the DNA (the blue print of the cell) from mitochondria (the cell’s battery). Mutations in this DNA are common and we can trace which cells possess which mutation. This permits us to work back in time and detect the origins of each cell. Furthermore, there are no validated means to predict the changes that lead to advanced precancerous Barrett’s. We propose that mutations acquired in mitochondria build up over time, and may reflect cancer risk and will follow patients over time to test this hypothesis and provide a better means to assess cancer risk and potentially decrease cumbersome endoscopic investigations.Who is collaborating with you on this project, in what capacity and where are they based? I have set up specific collaborations with 3 pathologists;Dr Marnix Jansen, Academic Medical Centre, Amsterdam. Dr Jansen is a pathologist who specialises in early cancer development. He is willing to provide frozen biopsies from patients who are routinely endoscoped with Barrett’s. Professor Marco Novelli, Dept Histopathology, University College London Hospitals. Prof Novelli is a pathologist with a proven track record of investigating relationships between cells in pre-cancerous disease. He has kindly agreed to provide snap frozen tissue from patient who have had surgery to remove their gullet because of cancer. Dr Manuel Ropdriguez-Justo, Dept Histopathology, University College London Hospitals. Dr Rodriguez-Justo is an expert gastrointestinal pathologist that has shown my host laboratory a great deal of support in providing fresh frozen specimens and assisting in obtaining consent from patients undergoing surgery. What will this project do and how long it will take?The project has 3 main studies/hypotheses to be investigated:Hypothesis 1 will use frozen gastrointestinal tissue taken from surgical resection/biopsies to compare single cells in Barrett’s glands and then whole glands between a small number of patients. It is difficult to predict how many patients will be required, however similar investigations in other organs has shown that between 5 and 15 patients will be required. This tissue has already been obtained. Next generation DNA sequencing and analysis of this data is expected to be complete within 12 months.Hypothesis 2 will require samples from no more than 10 patients. Different sites from each patient’s gullet and stomach will be compared to look for different mutations. DNA sequencing will be performed on these samples and data production and analysis is again estimated at 12 months.Hypothesis 3 will require samples over time from at least 25 patients. This will be analysed to determine mutations in cells over time. Recruitment for these patient and obtaining samples will begin on starting the project in year 1 and continue in to


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL