Molecular markers of the progression of intestinal metaplasia to gastric cancer

胃癌（GC）是全球癌症相关死亡的第二大常见原因。这是一种可以手术治疗的疾病，如果早期发现，预后良好。在我们的社区中，大多数患者在晚期才被发现，其中不到20%的患者存活5年。大多数胃癌发生前有不同的组织学阶段，从胃粘膜炎症、肠化生（IM）到最终的癌症。这些阶段的特点是遗传事件在很大程度上是未知的，发生的时间可能长达数年。同样明显的是，特别是在胃癌不那么普遍的国家，只有一部分人最终会患上胃癌。IM发展和GC诊断的长潜伏期为干预和研究导致GC的变化以及发现可能预测哪些个体将发展的基因提供了机会。在这个阶段，干预是很明显的。它很容易诊断，存在时间很长，对某些个体来说，最终会积累足够的遗传事件，从而导致进展为GC。对这些个体进行有针对性的筛查将成为发现早期胃癌的可行策略，并避免昂贵的非靶向筛查。本提案旨在找到负责IM向GC转变的关键遗传事件。第一步利用Affymetrix阵列检测IM中表达的与GC特异性相关的基因。这些候选药物将通过小鼠GC模型验证并用于研究它们在GC进展中的作用。本研究旨在寻找与GC相关的基因，这些基因可以用作：1)人类进展的标记，将被用作将个体分层到筛选方案的工具；2)有待动物实验的候选药物，以研究胃癌的发病机制，并有可能作为预防或治疗的靶点。

Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characterised by genetic events that are largely unknown and occur over a period that can take years. It is also evident, especially in countries where GC is not as prevalent, that only a proportion of individuals will eventually develop GC. The long latency from the develpoment of IM and diagnosis of GC offers an opportunity to intervene and study the changes that lead to GC as well as find genes that may predict which individuals will progress. IM is the stage in which intervention is obvious. It is very easily diagnosed, is present for a long time and, for certain individuals, will eventually accumulate enough genetic events that will mandate progression to GC. Targeted screening of these individuals will enable a feasible strategy to find early GC, and avoid costly non-targeted screening. This proposal seeks to find key genetic events responsible for the transition of IM to GC. The first step utilises Affymetrix arrays to detect genes expressed in IM and specifically linked to GC. These candidates will be validated and used to study their role in the progression to GC using a mouse model of GC. This study is designed to find genes responsible for GC that can be used as: 1) a marker of progression in humans that will be used as a tool to stratify individuals into a screening protocol; 2) candidates to be tested in animal studies to study the pathogenesis of GC and potentially used as preventative or therapeutic targets.