Gastric adenocarcinoma is the leading infection-associated cancer and third most common cause of global cancer mortality. Helicobacter pylori infects over half of the world's population and up to 85% of persons residing in developing nations, yet prevention programs and biomarkers are lacking to identify high risk strains and to manage patients with precancerous lesions. This Program Project Grant has made seminal contributions to gastric cancer research by utilizing extensive and well-organized infrastructures in Latin America, organized around a unique long-term cohort of human subjects from a former chemoprevention trial in the high cancer risk Andean region of Colombia. Central accomplishments include discoveries related to: 1) high risk (mountain) vs. low risk (coastal) cancer risk regions; 2) H. pylori strain phylogeographic origin and genetic mismatch between human hosts and the infecting strains that are directly linked with disease progression; 3) important disease modifiers including the gastric microbiota and concurrent parasitic infection; 4) a causal role for polyamines and specifically the oxidation of spermine by spermine oxidase (SMOX) as a cause of DNA damage, and the importance of phosphorylation of EGFR and ERBB2 as a molecular signature of gastric carcinogenesis. In this P01, in addition to the long-term follow-up of the high risk Colombian cohort, we will include new study populations in Central America, where NCI-funded infrastructures are in place, as this region represents the core low/middle income countries (LMICs) of Latin America with linkage to significant U.S. Hispanic immigrant populations. The overarching objective of this P01 renewal application is to develop new understanding of gastric carcinogenesis through studies incorporating analyses of human and H. pylori genetics, and gene methylation (Project 1), the interaction of H. pylori with parasitic infection and the gastric microbiota (Project 2), and molecular mechanisms of gastric carcinogenesis focused on novel pathways for oxidative DNA damage (Project 3). These projects each explore distinct hypothesis, but are tightly integrated in their focus on developing novel strategies for risk stratification and prevention of gastric cancer. The individua projects are: Project 1, Epidemiologic studies of gastric carcinogenesis (PI - Douglas M. Morgan); Project 2, The influence of gastric microbiota, intestinal helminths and host immune responses in cancer risk (PI - James G. Fox); Project 3, Molecular signatures of gastric carcinogenesis in the host response to H. pylori (PI - Keith T. Wilson). These studies are enriched by three cores: Histopathology (Core A); Administrative (Core B); and Fieldwork (Core C). The unique and highly developed expertise brought to this P01 includes global health and epidemiology, human and bacterial genetics, microbiology, immunology, cancer biology, pathology, and gastroenterology. Collectively, these cross-disciplinary studies are extremely well-positioned to bring to fruition bold and exciting new concepts in gastric cancer molecular epidemiology, with direct translational relevance to specific risk assessment and prevention strategies.
The main cause of gastric cancer is infection of the stomach with a bacterium, Helicobacter pylori, which occurs in more than half of the people in the world, and is especially common in Latin America and represents a major concern in Hispanic immigrants to the United States. Population eradication of Helicobacter pylori with antibiotic treatment is not feasible, does not always eradicate the infection, does not sufficiently reduce cancer risk once stomach pathology reaches a pre-cancerous stage, and has been associated with the causation of other diseases; thus there is a pressing need for new approaches to this problem. This Program Project Grant will utilize optimized on-site research programs to study human subjects in Colombia and Central America and establish the molecular basis for predicting cancer risk, including the genetics of the human host and the infecting bacteria, the presence of other bacteria in the stomach and infection with parasites, and specific responses in the stomach that may lead to cancer, all with the goal of devising new interventions to prevent cancer in persons at the highest risk in the USA, Latin America, and around the world.
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