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，具有明显的地域特征。 发病率的变化。感染幽门螺杆菌和cagA+菌株，尤其是- 公认的风险因素，但在拉丁美洲人口中非常普遍，不足以在- 有风险的病人。迫切需要开发生物标记物来识别那些在 慢性胃炎和癌前病变(萎缩、肠化生)疾病进展的最高风险 腺癌的分期。此前，该项目研究了一群独特的哥伦比亚人的长期队列 包括根除幽门螺杆菌的化学预防试验的受试者，我们最近证明 人类宿主和感染幽门螺杆菌菌株的基因祖先之间的不匹配(中断的共同作用) 进化论)与胃癌风险有关。此外，我们还发现，特定宿主基因的甲基化 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 幽门螺杆菌与人类宿主遗传相互作用决定，也由特定宿主基因预测 甲基化改变。我们将利用我们的高效和经济高效的研究基础设施 哥伦比亚和中美洲为这些高危人群的研究提供便利。我们的具体目标是：(一) 确定哥伦比亚长期化学预防中高危受试者的组织学进展率 一群人。我们将在未来五年内进行定期的主题家庭跟踪调查，并增加一项 在24岁时对受试者进行内窥镜评估，重点是有癌前病变的高危受试者。 我们将确定异型增生和癌的进展率，以及H。 幽门螺杆菌无感染期、再感染及菌株的组织病理学差异。(2)确定幽门螺杆菌是否- 人类遗传祖先的相互作用是高风险和低风险癌症风险的一个可概括的决定因素 中美洲的人口，正如我们在哥伦比亚观察到的那样。我们将招收一系列科目 从慢性胃炎到中美洲高危人群的腺癌等各种胃病 山区(梅斯蒂佐)和两个低风险沿海地区，即太平洋(梅斯蒂佐)和加勒比 (非洲)人口。我们将用高密度基因来描述人类和幽门螺杆菌的遗传祖先 分别使用全局诊断和有效的组织病理学进行阵列和全基因组测序 以评分作为结果衡量标准。(3)确定特定基因的DNA启动子甲基化水平是否 与哥伦比亚队列中的进展风险有关。我们将量化特定基因的DNA甲基化 基线和16年的基因启动子作为第20年和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的遗传祖先对中美洲甲基化的影响 患者组。我们期望这些研究能提供新的工具来识别罹患糖尿病风险升高的个体。 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.