Precision Interception of Gastric Cancer Precursors Through Molecular and Cellular Risk Stratification

摘要-总体 胃癌是世界范围内癌症发病率和死亡率的主要原因。幽门螺旋杆菌会 (Hp)是胃癌的最大危险因素，它的感染引发了体内的炎症级联反应。 胃微环境许多感染Hp的人会出现一种叫做胃癌的癌前病变， 肠化生（GIM），虽然有些人受到的影响最小，但其他人继续发展 浸润性胃癌关于Hp如何与胃粘膜相互作用， 微环境和促进胃癌，以及为什么GIM对患者构成可变风险。的重点 计划项目补助金（PPG）是表征胃上皮细胞的分子和基因组特征， 高危与低危胃癌前病变，Hp作为分层危险因素。PPG涉及三个 独特但协同的项目： (1)高危胃癌前病变的分子和细胞决定因素。 (2)胃癌前病变离体模型的建立。 (3)胃癌前病变的分子危险分层。 PPG多学科研究团队的领导者具有相关临床专业背景 传染病学、胃肠病学和胃肠肿瘤学。PPG广泛而深入地利用 在胃癌的单细胞测序、Hp生物学、流行病学和临床研究方面的研究专长 预防有几个强大的和协同的临床队列和生物标本库， PPG的基础。这些包括胃癌前病变的两个群组，胃癌前病变组和胃癌前病变组。 条件研究（GAPS，斯坦福大学）和NCI支持的胃癌前体病变研究 (GPCL，Pontificia Universidad Católica de Chile）、胃癌登记处（GCR，斯坦福大学），以及 NCI支持的Hp基因组计划（HpGP，范德比尔特大学）。翻译和临床项目， PPG提供了一种高影响精确拦截和癌症预防的新策略，以减少胃 癌症风险。PPG中的跨学科方法对于改善临床预防策略至关重要 降低胃癌的风险。

ABSTRACT – OVERALL Gastric cancer is a leading cause of cancer morbidity and mortality worldwide. The bacterium Helicobacter pylori (Hp) is the single greatest risk factor for gastric cancer, its infection triggering an inflammatory cascade within the gastric microenvironment. Many people infected with Hp develop a precancerous lesion called gastric intestinal metaplasia (GIM), and while some are minimally affected by the condition, others go on to develop invasive gastric cancer. There remain many unanswered questions about how Hp interacts with the gastric microenvironment and promotes gastric cancer, and why GIM poses variable risk to patients. The focus of this Program Project Grant (PPG) is characterizing the molecular and genomic features of gastric epithelial cells in high-risk versus low-risk gastric precancerous lesions, with Hp as a stratifying risk factor. The PPG involves three distinct yet synergistic projects: (1) Molecular and Cellular Determinant of High-Risk Gastric Precancerous Lesions. (2) Ex Vivo Modeling of Gastric Precancerous Lesions. (3) Molecular Risk Stratification of Gastric Precancerous Lesions. The leaders of the PPG’s multidisciplinary research teams have backgrounds in the relevant clinical specialties of infectious disease, gastroenterology and gastrointestinal oncology. The PPG leverages broad and deep research expertise in single-cell sequencing, Hp biology, epidemiology and clinical research for gastric cancer prevention. There are several robust and synergistic clinical cohorts and biospecimen repositories that make up the foundation of the PPG. These include two cohorts of gastric precancerous lesions, the Gastric Precancerous Conditions Study (GAPS, Stanford University) and the NCI-supported Gastric Cancer Precursor Lesions Study (GPCL, Pontificia Universidad Católica de Chile), the Gastric Cancer Registry (GCR, Stanford University), and the NCI-supported Hp Genome Project (HpGP, Vanderbilt University). The translational and clinical projects in the PPG offer a novel strategy of high-impact precision interception and cancer prevention to reduce gastric cancer risk. The interdisciplinary approach in this PPG is essential for improving clinical prevention strategies and risk attenuation of gastric cancer.