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

科学与医学背景胃癌(GC)是一种迫切需要新研究的疾病，以开发一种更个性化的方法，在癌症发展之前对患者进行风险分层。尽管自20世纪90年代初以来，胃癌的发病率有所下降，但存活率仍然很低，只有不到五分之一(19%)的患者存活了5年或更长时间。大多数人是在疾病的晚期被诊断出来的(69-75%在3期或4期)，这使得治疗选择有限。我们知道，胃壁的变化可能比GC的发展早几年。这是由于感染(幽门螺杆菌)导致慢性炎症，导致萎缩性胃炎和胃肠化生(GIM)，这两种疾病都是癌前状态，癌症风险增加。很可能，填充和补充快速更新的胃壁的干细胞对于这些癌前疾病的传播和确定癌症的发展风险至关重要。这些干细胞所面临的长期发炎的恶劣环境可能会导致正常细胞被替换为“癌症启动”的细胞类型，少数细胞偶尔会获得肿瘤发展所需的特征。虽然幽门螺杆菌感染很常见，但患癌症的个人比例很小(每年0.5%)。在英国，没有GC的筛查计划，但被发现有严重癌前变化的患者被登记参加定期内窥镜检查计划，这对患者来说是不愉快的，医疗服务成本也很高，因为大多数患者从未患上GC，而且生存益处的证据有限最近内窥镜技术的进步可以更准确地检测GIM，我们的研究团队目前正在研究一种新的内窥镜方法，使用“图像增强”的内窥镜来更准确和可靠地诊断这些情况。为了从改进的诊断技术中受益，必须解决我们对癌症前如何进展到癌症的理解中的差距，以便能够准确预测癌症的发展风险。研究计划这个奖学金占据了宝贵的地位，结合了我们UCLH研究团队在上消化道癌症方面的临床专业知识，可以接触到现有的癌症前疾病患者队列，以及UCL&Barts癌症研究所内的科学专业知识，他们在基因组学和癌症进化方面拥有经过证明的跟踪记录。这项研究将分析12个胃的样本，这些样本来自接受过GC手术的患者。然后，将对12个“正常”胃的匹配队列进行分析，这些胃来自于因减肥手术而切除胃的患者。这将使比较正常和GIM中的干细胞特性，以及癌症前期的基因变化成为可能。随后，我们将分析40例在UCLH接受慢性胃炎监测的患者的多区域胃活检(我们的临床估计研究)，以将结果与临床数据相关联。这项研究的最终目的是开发一种在癌症发生之前预测癌症风险的模型。这项研究将调查供应胃壁的干细胞的行为，包括填充在癌症前状态(肠化生)中的突变干细胞，这将有助于弥合我们对GC发展的理解差距，从而使更个性化的方法能够评估患者的风险。这项研究将检查癌症前积累的基因变化，以了解这种情况可能如何演变为癌症。这是第一项旨在同时分析癌前状态下遗传和干细胞行为变化并将其与临床诊断相关联的研究，这将有助于风险预测模型的创建，该模型将对研究癌症前病变具有更广泛的意义。

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