Etiological Studies of Gastric Carcinoma

描述（由申请人提供）：胃腺癌是主要的感染相关癌症，也是全球癌症死亡率的第三大常见原因。幽门螺杆菌感染了超过一半的世界人口和高达85%的居住在发展中国家的人，但缺乏预防计划和生物标志物来识别高风险菌株和管理患有癌前病变的患者。该计划项目赠款通过利用拉丁美洲广泛和组织良好的基础设施，为胃癌研究做出了开创性的贡献，这些基础设施围绕来自哥伦比亚高癌症风险安第斯地区的前化学预防试验的人类受试者的独特长期队列组织。主要成就包括与以下方面有关的发现：1）高风险（山区）与低风险（沿海）癌症风险地区; 2）H。幽门螺杆菌菌株的地理来源和人类宿主与感染菌株之间的遗传错配与疾病进展直接相关; 3）重要的疾病修饰因子，包括胃微生物群和并发寄生虫感染; 4）多胺的因果作用，特别是精胺氧化酶（SMOX）对精胺的氧化作为DNA损伤的原因，以及EGFR和ERBB 2磷酸化作为胃癌发生的分子标志的重要性。在本P01中，除了高风险哥伦比亚队列的长期随访外，我们还将纳入中美洲的新研究人群，该地区已建立了NCI资助的基础设施，因为该地区代表了拉丁美洲的核心低/中等收入国家（LMIC），与美国西班牙裔移民人口有很大联系。本次P01更新申请的总体目标是通过对人类和H. pylori遗传学、基因甲基化（Project 1）、H.幽门螺杆菌与寄生虫感染和胃微生物群（项目2），胃癌发生的分子机制集中在氧化DNA损伤的新途径（项目3）。这些项目各自探索不同的假设，但在其重点发展新的风险分层和预防胃癌的策略是紧密结合的。项目1，胃癌发生的流行病学研究（PI -道格拉斯M. Morgan）;项目2，胃微生物群、肠道蠕虫和宿主免疫应答对癌症风险的影响（PI - James G. Fox）;项目3，宿主对H. pylori（PI -基思T. Wilson）。这些研究由三个核心丰富：历史学（核心A）;行政（核心B）;和实地考察（核心C）。P01带来的独特和高度发达的专业知识包括全球健康和流行病学，人类和细菌遗传学，微生物学，免疫学，癌症生物学，病理学和胃肠病学。总的来说，这些跨学科的研究非常适合在胃癌分子流行病学中实现大胆和令人兴奋的新概念，并与特定的风险评估和预防策略直接相关。

DESCRIPTION (provided by applicant): Gastric adenocarcinoma is the leading infection-associated cancer and third most common cause of global cancer mortality. Helicobacter pylori infects over half of the world's population and up to 85% of persons residing in developing nations, yet prevention programs and biomarkers are lacking to identify high risk strains and to manage patients with precancerous lesions. This Program Project Grant has made seminal contributions to gastric cancer research by utilizing extensive and well-organized infrastructures in Latin America, organized around a unique long-term cohort of human subjects from a former chemoprevention trial in the high cancer risk Andean region of Colombia. Central accomplishments include discoveries related to: 1) high risk (mountain) vs. low risk (coastal) cancer risk regions; 2) H. pylori strain phylogeographic origin and genetic mismatch between human hosts and the infecting strains that are directly linked with disease progression; 3) important disease modifiers including the gastric microbiota and concurrent parasitic infection; 4) a causal role for polyamines and specifically the oxidation of spermine by spermine oxidase (SMOX) as a cause of DNA damage, and the importance of phosphorylation of EGFR and ERBB2 as a molecular signature of gastric carcinogenesis. In this P01, in addition to the long-term follow-up of the high risk Colombian cohort, we will include new study populations in Central America, where NCI-funded infrastructures are in place, as this region represents the core low/middle income countries (LMICs) of Latin America with linkage to significant U.S. Hispanic immigrant populations. The overarching objective of this P01 renewal application is to develop new understanding of gastric carcinogenesis through studies incorporating analyses of human and H. pylori genetics, and gene methylation (Project 1), the interaction of H. pylori with parasitic infection and the gastric microbiota (Project 2), and molecular mechanisms of gastric carcinogenesis focused on novel pathways for oxidative DNA damage (Project 3). These projects each explore distinct hypothesis, but are tightly integrated in their focus on developing novel strategies for risk stratification and prevention of gastric cancer. The individua projects are: Project 1, Epidemiologic studies of gastric carcinogenesis (PI - Douglas M. Morgan); Project 2, The influence of gastric microbiota, intestinal helminths and host immune responses in cancer risk (PI - James G. Fox); Project 3, Molecular signatures of gastric carcinogenesis in the host response to H. pylori (PI - Keith T. Wilson). These studies are enriched by three cores: Histopathology (Core A); Administrative (Core B); and Fieldwork (Core C). The unique and highly developed expertise brought to this P01 includes global health and epidemiology, human and bacterial genetics, microbiology, immunology, cancer biology, pathology, and gastroenterology. Collectively, these cross-disciplinary studies are extremely well-positioned to bring to fruition bold and exciting new concepts in gastric cancer molecular epidemiology, with direct translational relevance to specific risk assessment and prevention strategies.