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 胃癌导致非西班牙裔癌症发病率的第三大差异 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 - 任何癌症的死亡率差异最高。作为高度致命的癌症，胃癌 是非洲裔美国男性癌症死亡的第六个主要原因。大多数胃癌是由 幽门螺杆菌（H. Pylori）感染，在非裔美国人中比白人更常见。改进 了解幽门螺杆菌的免疫响应尚未转化为筛查，监视， 或预防癌症。确实，目前，美国没有胃癌筛查的策略和 监视。一系列事件导致幽门螺杆菌感染引发的胃癌，然后发生变化 包括慢性胃炎，肠道化生（IM），发育不良和癌症。目前，关于如何 种族介导的对幽门螺杆菌感染的反应差异可能导致胃癌风险增加。这是 例如，已知幽门螺杆菌病毒因子，例如细胞毒性相关的基因，CAGA以及更多 吸气细胞毒素A，VACA，干扰宿主自适应免疫系统的有力形式，使幽门螺杆菌 胃粘膜定植。此外，某些CAGA/VACA基因型与胃增加有关 炎症和上皮变性。我们自己的初步数据表明，非裔美国人有 增加对CAGA和VACA的抗体反应增加，这与化生的风险增加有关 发育不良。但是，种族相关遗传因素（例如IL-1β）的机制 多态性，与前体病变进展的其他病毒因素有关和发病机理 胃癌尚不清楚。我们的目标是解决这些知识差距并翻译生物学发现 制定新的筛查和监视策略，以解决种族分布和 改善与胃癌有关的生存。我们假设非洲裔美国人的幽门螺杆菌感染更多 可能会导致免疫激发，从而增加肠道化生的风险，发育异常和演变 细胞毒性T细胞反应解释了失速癌症事件和死亡率的潜在差异。我们将 创建回顾性队列并检验以下假设：基于组织的免疫反应的种族差异 沿着胃癌发生级联反应与更晚期疾病相关（AIM 1）；并前瞻性 比较新鲜血清和组织样品中宿主对幽门螺杆菌的宿主反应的种族差异（AIM 2）。这个项目 将开发新的风险标记，以适用于伴有幽门螺杆菌病毒的风险分层策略 因素和高风险非裔美国人中发现的免疫签名，作为减少的关键一步 胃癌筛查，监视和预防的差异差距。