Precision Interception of Gastric Cancer Precursors Through Molecular and Cellular Risk Stratification

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ABSTRACT – OVERALL Gastric cancer is a leading cause of cancer morbidity and mortality worldwide. The bacterium Helicobacter pylori (Hp) is the single greatest risk factor for gastric cancer, its infection triggering an inflammatory cascade within the gastric microenvironment. Many people infected with Hp develop a precancerous lesion called gastric intestinal metaplasia (GIM), and while some are minimally affected by the condition, others go on to develop invasive gastric cancer. There remain many unanswered questions about how Hp interacts with the gastric microenvironment and promotes gastric cancer, and why GIM poses variable risk to patients. The focus of this Program Project Grant (PPG) is characterizing the molecular and genomic features of gastric epithelial cells in high-risk versus low-risk gastric precancerous lesions, with Hp as a stratifying risk factor. The PPG involves three distinct yet synergistic projects: (1) Molecular and Cellular Determinant of High-Risk Gastric Precancerous Lesions. (2) Ex Vivo Modeling of Gastric Precancerous Lesions. (3) Molecular Risk Stratification of Gastric Precancerous Lesions. The leaders of the PPG’s multidisciplinary research teams have backgrounds in the relevant clinical specialties of infectious disease, gastroenterology and gastrointestinal oncology. The PPG leverages broad and deep research expertise in single-cell sequencing, Hp biology, epidemiology and clinical research for gastric cancer prevention. There are several robust and synergistic clinical cohorts and biospecimen repositories that make up the foundation of the PPG. These include two cohorts of gastric precancerous lesions, the Gastric Precancerous Conditions Study (GAPS, Stanford University) and the NCI-supported Gastric Cancer Precursor Lesions Study (GPCL, Pontificia Universidad Católica de Chile), the Gastric Cancer Registry (GCR, Stanford University), and the NCI-supported Hp Genome Project (HpGP, Vanderbilt University). The translational and clinical projects in the PPG offer a novel strategy of high-impact precision interception and cancer prevention to reduce gastric cancer risk. The interdisciplinary approach in this PPG is essential for improving clinical prevention strategies and risk attenuation of gastric cancer.