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

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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.