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

胃癌进展的定量模型：研究慢性炎症胃内肠化生的演变。

• 批准号: MR/S022244/1
• 负责人: William Waddingham
• 金额: $ 21.52万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS022244%2F1
• 关键词: quantitative; model; gastric; cancer; progression

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

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GC的发病率有所下降，但生存率仍然很差，只有不到五分之一（19%）的患者在疾病中存活5年或更长时间。大多数人在疾病的晚期被诊断出来（69-75%在3或4期），使治疗选择有限。我们知道胃粘膜的变化可以早于GC的发展数年。这是由于感染（H。幽门螺杆菌）引起慢性炎症，导致称为萎缩性胃炎和胃肠道化生（GIM）的病症，这两种癌前病症都具有增加的癌症风险。很可能，干细胞填充并补充快速更新的胃粘膜对于这些癌前疾病的传播和确定癌症发展的风险至关重要。这些干细胞所面临的敌对的慢性炎症环境可能会导致正常细胞被“癌症引发”细胞类型所取代，少数细胞偶尔会获得肿瘤发展所需的特征。而H.幽门螺杆菌感染很常见，患癌症的比例很小（<0.5%/年）。在英国，没有GC的筛查计划，但发现有严重癌前变化的患者被纳入定期内窥镜检查的监测计划，这对患者来说是不愉快的，对医疗保健服务来说是昂贵的，因为大多数患者从未发生GC，并且生存益处的证据有限。我们的研究小组现正研究一种新的内窥镜检查方法，利用“影像增强的内窥镜检查，以更准确可靠地诊断这些病症。为了从改进的诊断技术中受益，我们必须解决我们对癌前病变如何发展为癌症的理解中的差距，以便准确预测癌症发展的风险。研究计划该奖学金将UCLH研究团队在上消化道癌症方面的临床专业知识与现有的癌前病变患者队列相结合，以及UCL & Barts癌症研究所的科学专业知识，在基因组学和癌症演变方面有着良好的记录。这项研究将分析来自接受过GC手术的患者的12个胃的样本。然后将对12个“正常”胃的匹配队列进行分析，这些胃来自接受过胃切除术的患者。这将能够比较正常与GIM中的干细胞特性，以及癌前病变中的遗传变化。从这一点，多区域胃活检40例慢性胃炎在UCLH监测（我们的临床ESTIMATE研究）将进行分析，以相关的结果与临床数据。这项研究的最终目的是开发一种模型，在癌症发生之前预测癌症风险。这项研究将调查供应胃壁的干细胞的行为，包括填充癌前状态（肠化生）的突变干细胞，这将有助于弥合我们对GC发展的理解，从而实现更个性化的方法来评估患者的风险。这项研究将检查癌症前积累的遗传变化，以告知我们对这种情况如何演变为癌症的理解。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，这将为创建风险预测模型提供信息，该模型将对研究癌前状态具有更广泛的意义。

项目成果

Recent advances in the detection and management of early gastric cancer and its precursors.

• DOI: 10.1136/flgastro-2018-101089
• 发表时间: 2021
• 期刊: Frontline gastroenterology
• 影响因子: 2.6
• 作者: Waddingham W;Nieuwenburg SAV;Carlson S;Rodriguez-Justo M;Spaander M;Kuipers EJ;Jansen M;Graham DG;Banks M
• 通讯作者: Banks M

Mistakes in gastric polyps and how to avoid them

胃息肉的误区及避免方法

• 发表时间: 2021
• 期刊: UEG Education
• 作者: W Waddingham

Accuracy of endoscopic staging and targeted biopsies for routine gastric intestinal metaplasia and gastric atrophy evaluation study protocol of a prospective, cohort study: the estimate study.

一项前瞻性队列研究的常规胃肠化生和胃萎缩评估研究方案的内镜分期和靶向活检的准确性：估计研究。

• DOI: 10.1136/bmjopen-2019-032013
• 发表时间: 2019
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Nieuwenburg SAV

Quantifying the Clonal Expansion of Gastric Intestinal Metaplasia in vivo at Single Cell Resolution

以单细胞分辨率定量体内胃肠化生的克隆扩张

• 发表时间: 2019
• 作者: Waddingham W

Defining the clonal origin, expansion rate, and clonal diversity of intestinal metaplasia in the helicobacter-infected human stomach

定义幽门螺杆菌感染的人胃中肠化生的克隆起源、扩增率和克隆多样性

• 发表时间: 2019
• 作者: Waddingham W