Project 1 - Epidemiologic studies of gastric carcinogenesis

项目1-摘要： 胃腺癌是全球癌症死亡的主要原因之一，具有显著的地理分布特征。 发病率的变化。感染幽门螺杆菌和cagA+菌株，特别是，是很好的- 公认的风险因素，但在拉丁美洲人群中非常普遍，不足以描述- 风险患者。迫切需要开发生物标志物，用于鉴定处于以下状态的个体： 慢性胃炎和癌前病变（萎缩、肠上皮化生）的疾病进展风险最高 阶段为腺癌。此前，该项目研究了一个独特的长期队列的哥伦比亚 受试者在化学预防试验中，包括H.幽门螺杆菌根除，我们最近已经证明， 人类宿主的遗传祖先与感染H. pylori菌株（破坏的共- 进化）与胃癌风险相关。此外，我们还发现特定宿主基因甲基化 胃粘膜的异常可能是进展风险的标志。我们假设癌症风险是 由H. pylori与人类宿主的遗传相互作用，也可由特定的宿主基因预测 甲基化改变我们将利用我们的高生产力和成本效益的研究基础设施， 哥伦比亚和中美洲，以促进在这些高风险人群的研究。我们的具体目标是：（1） 确定长期哥伦比亚化学预防中高风险受试者的组织学进展率 队列。我们将在未来5年内定期对受试者家庭进行随访， 在第24年对受试者进行内镜评估，重点关注具有癌前病变的最高风险受试者。 我们将确定进展为异型增生和癌的比率以及H的持续时间和时间的影响。 幽门螺杆菌无感染期、再感染期及菌株间组织病理学差异。(2)确定H.幽门- 人类遗传祖先相互作用是高风险和低风险癌症风险的普遍决定因素 中美洲的人口，正如我们在哥伦比亚所观察到的那样。我们将招募受试者， 从慢性胃炎到腺癌的胃病变，来自高危中美洲 山区（梅斯蒂索）和两个低风险沿海地区，即太平洋（梅斯蒂索）和加勒比 （非洲）人口。我们将描述人类和H。幽门螺杆菌遗传祖先与高密度遗传 阵列和全基因组测序，分别使用全局诊断和经验证的组织病理学 作为结果的衡量标准。(3)为了确定特定基因的DNA启动子甲基化水平是否是 与哥伦比亚队列的进展风险相关。我们将定量DNA甲基化的具体 基线和第16年的基因启动子作为第20年和第24年组织病理学进展的预测因子。我们 还将探讨人类和细菌遗传祖先对中美洲甲基化的影响 患者组。我们希望这些研究能提供新的工具来识别具有高风险的个体， 胃癌

PROJECT 1- Summary: Gastric adenocarcinoma is one of the leading global causes of cancer mortality, with marked geographic variation in incidence rates. Infection with Helicobacter pylori, and cagA+ strains, specifically, are well- recognized risk factors, but are highly prevalent in Latin American populations, and insufficient to delineate at- risk patients. There is a critical need to develop biomarkers for the identification of individuals who are at highest risk for disease progression from chronic gastritis and precancerous (atrophy, intestinal metaplasia) stages to adenocarcinoma. Previously, this project has studied a unique long-term cohort of Colombian subjects in chemoprevention trial which included H. pylori eradication, and we have recently demonstrated that the mismatch between genetic ancestries of the human host and the infecting H. pylori strain (disrupted co- evolution) is associated with gastric cancer risk. Further, we have found that specific host gene methylation abnormalities in gastric mucosae may be markers of progression risk. We hypothesize that cancer risk is determined by H. pylori and human host genetic interactions, and also is predicted by specific host gene methylation alterations. We will utilize our highly productive and cost-effective research infrastructures in Colombia and Central America to facilitate studies in these high risk populations. Our specific aims are: (1) To determine the rate of histologic progression of high risk subjects in the long-term Colombian chemoprevention cohort. We will perform regular subject household follow-up over the next 5 years and one additional endoscopic assessment of subjects at year 24, with a focus on highest risk subjects with precancerous lesions. We will determine rates of progression to dysplasia and carcinoma and the effect of duration and timing of H. pylori infection-free period, re-infection and strain differences on histopathology. (2) To determine if H. pylori– human genetic ancestry interactions are a generalizable determinant of cancer risk in high and low risk populations in Central America, as we have observed in Colombia. We will enroll subjects with a range of gastric lesions ranging from chronic gastritis to adenocarcinoma from the high risk Central American mountainous (Mestizo) region and two low risk coastal regions, namely Pacific (Mestizo) and Caribbean (African) populations. We will characterize human and H. pylori genetic ancestry with high-density genetic arrays and whole genome sequencing, respectively, using global diagnosis and the validated histopathology score as the outcome measures. (3) To determine if DNA promoter methylation levels of specific genes are associated with the risk of progression in the Colombian cohort. We will quantify DNA methylation of specific gene promoters at baseline and year 16 as predictors of histopathologic progression at years 20 and 24. We will also explore the influence of human and bacterial genetic ancestry on methylation in the Central America patient group. We expect these studies to provide novel tools to identify individuals with elevated risk for gastric cancer.