Project 2: Racial differences in host immune response and gastric carcinogenesis: Translating underlying biology to promote gastric cancer interception

项目2：宿主免疫反应和胃癌发生的种族差异：转化基础生物学以促进胃癌拦截

• 批准号: 10263344
• 负责人: MEIRA EPPLEIN
• 金额: $ 29.01万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263344
• 关键词: 3-Dimensional; Adaptive Immune System; Address; African American; Antibodies; Antibody Response; Antigens; Atrophic Gastritis; Biological; Biology; Cause of Death; Cells; Chronic Gastritis; Clinical; Coculture Techniques; Complex; Cytotoxic T-Lymphocytes; Cytotoxin; Data; Data Set; Dysplasia; Epithelial; Event; Foundations; Future; Gastric mucosa; Gastritis; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Helicobacter Infections; Helicobacter pylori; Helicobacter pylori induced gastric cancer; IL8 gene; Immune; Immune response; Incidence; Individual; Infection; Inflammatory; Intercept; Interleukin-1 beta; Interleukin-10; Interleukin-17; Interleukin-6; Intestinal Intraepithelial Neoplasia; Intestinal Metaplasia; Knowledge; Lesion; Malignant Neoplasms; Mediating; Metaplasia; Not Hispanic or Latino; Pathogenesis; Pathologic; Patients; Pattern; Pepsinogens; Prevention; Process; Race; Regulatory T-Lymphocyte; Retrospective cohort; Risk; Risk Factors; Risk Marker; Screening for Gastric Cancer; Serum; Specimen; Stomach; System; T cell response; TNF gene; Testing; Tissue Sample; Tissues; Transforming Growth Factor beta; Translating; Tumor-infiltrating immune cells; Virulence; Virulence Factors; Virulent; advanced disease; base; cancer health disparity; cancer prevention; cancer risk; clinical practice; cytokine; cytotoxic; disparity reduction; gastric carcinogenesis; gastric intestinal metaplasia; gastric organoids; high risk; improved; individualized prevention; macrophage; malignant stomach neoplasm; men; mortality; mortality disparity; novel; patient population; population based; programmed cell death ligand 1; prospective; racial difference; racial disparity; response; risk stratification; screening; serological marker; surveillance strategy; translational approach

ABSTRACT – Project 2 Gastric cancer is responsible for the third largest disparity in cancer incidence rates between Non-Hispanic African Americans and whites. More importantly, African Americans are more than twice as likely to die from gastric cancer than whites – the highest mortality disparity of any cancer. As a highly fatal cancer, gastric cancer is the 6th leading cause of death from cancer among African American men. Most gastric cancers are caused by Helicobacter pylori (H. pylori) infection, which is more common among African Americans than whites. Improved understanding of the immune response to H. pylori has not translated into advances in screening, surveillance, or cancer prevention. Indeed, Currently, the US does not have a strategy for gastric cancer screening and surveillance. A cascade of events leads to gastric cancer, initiated by H. pylori infection, followed by changes including chronic gastritis, intestinal metaplasia (IM), dysplasia, and cancer. Currently, little is known about how racially mediated differences in response to H. pylori infection might result in increased gastric cancer risk. It is known, for instance, that H. pylori virulence factors such as cytotoxic associated geneA, CagA, as well as more virulent forms of vacuolating cytotoxin A, VacA, interfere with the host adaptive immune system to allow H. pylori colonization in gastric mucosa. Moreover, certain CagA/VacA genotypes are associated with increased gastric inflammation and epithelial degeneration. Our own preliminary data demonstrate that African Americans have increased antibody responses to CagA and VacA, which correlate with increased risk of metaplasia and dysplasia. However, the mechanisms through which race-associated genetic factors, such as IL-1β polymorphism, relate to other virulence factors in the progression of precursor lesions and the pathogenesis of gastric cancer are unknown. Our goal is to address these knowledge gaps and translate biologic findings into new screening and surveillance strategies for clinical practice in order to address racial disparities and improve survival related to gastric cancer. We hypothesize that H. pylori infection in African Americans is more likely to result in an immune response that increases risk of intestinal metaplasia, dysplasia and evasion of cytotoxic T cell response, explaining the underlying disparity in stomach cancer incidence and mortality. We will create a retrospective cohort and test the hypothesis that racial differences in tissue-based immune response along the gastric carcinogenesis cascade correlate with more advanced disease (Aim 1); and prospectively compare racial differences in host response to H. pylori in fresh serum and tissue samples (Aim 2). This Project will develop novel risk markers to be applied to a risk-stratification strategy that incorporates H. pylori virulence factors and the immune-based signature found in high-risk African Americans, as a key step toward reducing the disparity gap in gastric cancer screening, surveillance, and prevention.

摘要-项目2 胃癌是非西班牙裔美国人之间癌症发病率第三大差异的原因。 非裔美国人和白人。更重要的是，非洲裔美国人死于 胃癌比白人-死亡率差距最大的任何癌症。胃癌作为一种高致命性癌症， 是非洲裔美国人癌症死亡的第六大原因。大多数胃癌是由 幽门螺杆菌（H. pylori）感染，这在非洲裔美国人中比白人更常见。改进 了解对H的免疫反应。幽门螺杆菌并没有转化为筛查，监测， 或癌症预防。事实上，目前，美国没有胃癌筛查的策略， 监视一系列事件导致胃癌，由H。幽门螺杆菌感染，随后发生变化 包括慢性胃炎、肠上皮化生（IM）、异型增生和癌症。目前，人们对如何做到这一点知之甚少 种族介导的对H. pylori感染可能导致胃癌风险增加。是 已知，例如，H.幽门螺杆菌毒力因子，如细胞毒性相关基因A，CagA，以及更多 毒力形式的空泡细胞毒素A，VacA，干扰宿主的适应性免疫系统，使H.幽门 在胃粘膜中定植。此外，某些CagA/VacA基因型与胃排空增加相关。 炎症和上皮变性。我们自己的初步数据表明，非洲裔美国人 对CagA和VacA的抗体应答增加，这与化生风险增加相关， 发育不良然而，种族相关的遗传因素，如IL-1β， 多态性，与其他毒力因子在前驱病变的进展和发病机制有关 胃癌的病因尚不清楚。我们的目标是填补这些知识空白，并将生物学发现转化为 为临床实践提供新的筛查和监测策略，以解决种族差异， 提高胃癌相关生存率。我们假设H.非裔美国人的幽门螺杆菌感染率 可能会导致免疫反应，增加肠化生，发育不良和逃避的风险， 细胞毒性T细胞反应，解释了胃癌发病率和死亡率的潜在差异。我们将 建立一个回顾性队列，并检验组织免疫反应的种族差异 沿着胃癌发生级联与更晚期疾病相关（目的1）;并且前瞻性地 比较宿主对H.幽门螺杆菌在新鲜血清和组织样品（目的2）。这个项目 将开发新的风险标志物，应用于风险分层策略，包括H。幽门毒力 在高危非洲裔美国人中发现的基于免疫的特征，作为减少 胃癌筛查、监测和预防方面的差距。