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

摘要-项目2 胃癌是非西班牙裔美国人癌症发病率的第三大差异。 美国黑人和白人。更重要的是，非裔美国人死于 胃癌的死亡率高于白人--是所有癌症中死亡率差距最大的。作为一种高度致命的癌症，胃癌 是非洲裔美国男性第六大癌症死因。大多数胃癌是由 幽门螺杆菌感染，在非裔美国人中比白人更常见。改进 对幽门螺杆菌免疫反应的了解并未转化为筛查、监测、 或者是癌症预防。事实上，目前美国没有胃癌筛查和治疗的战略。 监视系统。一系列事件导致胃癌，由幽门螺杆菌感染引发，随后发生变化 包括慢性胃炎、肠化生、不典型增生和癌症。目前，人们对此知之甚少。 种族因素对幽门螺杆菌感染反应的差异可能会导致胃癌风险的增加。它是 例如，已知幽门螺杆菌毒力因子，如细胞毒相关基因A、CagA以及更多 毒力形式的空泡化细胞毒素A，VacA，干扰宿主适应性免疫系统，允许H. 在胃粘膜的定植。此外，某些CagA/VacA基因型与胃病增加有关 炎症和上皮变性。我们自己的初步数据表明，非裔美国人 对CagA和VacA的抗体应答增加，这与化生和 发育不良。然而，种族相关遗传因素，如IL-1β 多态，与其他毒力因子在前驱病变的进展和发病机制中有关 胃癌的发病率是未知的。我们的目标是解决这些知识差距，并将生物学发现 为临床实践引入新的筛查和监测战略，以解决种族差异和 提高与胃癌相关的生存率。我们假设，非裔美国人感染幽门螺杆菌的比例更高 可能导致免疫反应，增加肠化生、异型增生和逃避 细胞毒性T细胞反应，解释了胃癌发病率和死亡率之间的潜在差异。我们会 建立一个回溯性队列，并检验种族差异在组织免疫反应中的假设 沿着胃癌发生的级联过程与更晚期的疾病相关(目标1)； 比较新鲜血清和组织样本中宿主对幽门螺杆菌的反应的种族差异(目标2)。本项目 将开发新的风险标记物，应用于结合幽门螺杆菌毒力的风险分层策略 在高危非裔美国人中发现的因素和基于免疫的特征，作为减少 在胃癌筛查、监测和预防方面的差距。

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.