A quantitative model of gastric cancer progression: investigating the evolution of intestinal metaplasia within the chronically inflamed stomach.

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Scientific & Medical ContextGastric cancer (GC) is a disease in urgent need of novel research to develop a more personalised approach to risk stratifying patients before cancer develops. Despite a decline in rates of GC since the early 1990s, survival remains poor with less than a fifth (19%) of patients surviving their disease for 5 years or more. Most are diagnosed at a late stage in their disease (69-75% at stage 3 or 4) making treatment options limited. We know that changes in the stomach lining can predate the development of GC by several years. These are due to an infection (H. Pylori) causing chronic inflammation, resulting in conditions known as atrophic gastritis and gastric intestinal metaplasia (GIM), both pre-cancerous conditions with an increased risk of cancer. It is likely that stem cells which populate and replenish the rapidly renewing stomach lining are essential to the spread of these pre-cancerous conditions and to determining the risk of development of cancer. The hostile chronically inflamed environment these stem cells face can result in replacement of the normal cells to a "cancer-primed" cell type, with a small number occasionally acquiring the characteristics needed for tumour development. While H. Pylori infection is common, the proportion of individuals who develop cancer is small (<0.5%/year). In the UK there is no screening programme for GC, but patients found to have severe pre-cancer changes are enrolled into a surveillance programme of regular endoscopies, this is unpleasant for the patient and costly for healthcare services with most patients never developing GC, and limited evidence for survival benefitRecent advances in endoscopy technology allow more accurate detection of GIM, our research team is currently studying a new endoscopic approach using "image enhanced" endoscopy to diagnose these conditions more accurately and reliably. In order to benefit from improved diagnostic techniques, gaps in our understanding of how pre-cancer progresses to cancer must be addressed, to allow accurate prediction of risk of cancer development.Research PlanThis Fellowship occupies a valuable position combining clinical expertise in upper gastro-intestinal cancer from our UCLH research team, with access to an existing cohort of patients with pre-cancer, and the scientific expertise within the UCL & Barts Cancer Institutes, with proven track records in genomics and cancer evolution. This study will analyse samples from an established set of 12 stomachs from patients who have undergone surgery for GC. Analysis will then be performed of a matched cohort of 12 "normal" stomachs from patients who have undergone removal of their stomach for bariatric surgery. This will enable comparison of stem cell properties in normal vs GIM, and the genetic changes in pre-cancer. Following on from this, multiregion gastric biopsies in 40 patients having surveillance for chronic gastritis at UCLH (our clinical ESTIMATE Study) will be analysed to correlate findings with clinical data.Research Aims1. The ultimate aim of this research is to develop a model for predicting cancer risk before cancer has developed. This research will investigate the behaviour of stem cells that supply the stomach lining, including the mutated stem cells that populate the pre-cancer state (intestinal metaplasia), this will help bridge the gaps in our understanding of GC development, thereby enabling a more personalised approach to assessing patient's risk.2. This study will examine the genetic changes that accumulate before cancer to inform our understanding of how this condition might evolve into cancer.3. This is the first research study aiming to simultaneously analyse the changes in genetic and stem cell behaviour within the pre-cancer state and correlate these with clinical diagnosis, this will inform creation of a risk-prediction model that will have wider implications for studying pre-cancer in genera