Gastric cancer is the second most deadly cancer in the world, and incidence and mortality rates are highest in East Asia. Infection with Helicobacter pylori, the strongest known risk factor for gastric cancer, is also endemic throughout East Asia, but only a small percentage of infected individuals ever develop gastric cancer. Due to the high level of genetic variation among H. pylori isolates, it may be possible to identify risk markers tht could classify H. pylori-infected individuals into high- and low-risk groups, presenting a unique opportunity for cost- effective disease prevention. This is especially significant because H. pylor eradication has been found to effectively reduce gastric cancer incidence. Currently, however, there is no known biomarker that is feasibly assessed that can estimate a substantially significant increase in risk for gastric cancer. Recently, we performed a pilot study nested in a prospective Chinese cohort to identify potential H. pylori blood biomarkers. Utilizing novel H. pylori multiplex serology, we found that increasing number of sero-positive results to six H. pylori proteins (Omp, HP0305, HyuA, HpaA, CagA, and VacA) may be a novel biomarker panel for gastric cancer risk. We have found that this biomarker panel is significantly stronger at discriminating risk than evidence of the CagA protein alone, resulting in those individuals with antibodies to all six indicated H. pylori proteins having a three- to five-fold increase in risk of distal gastric cancer. Replication of these results in other populations, particularly other high-rsk East Asian populations who may be colonized by similar Asian strains, would enhance the possibility of utilizing these H. pylori blood biomarkers for gastric cancer screening. Thus, we have assembled a consortium of eight prospective cohort studies in the high gastric cancer-incidence populations of China, Japan, and Korea, to determine if we can replicate this novel biomarker panel for gastric cancer risk. We aim to: assess the association of H. pylori protein antibody levels in pre-diagnostic blood samples with gastric cancer risk in 2,000 distal gastric cancer cases and 2,000 controls in East Asia; determine if host factors of inflammation or susceptibility to inflammation aid in assessing gastric cancer risk; and build a predictive model for gastric cancer risk in East Asia that includes H. pylori blood biomarkers and enables us to categorize individuals into high and low-risk groups for gastric cancer, and then validate this model among individuals with both cancer and precancerous lesions in a high-risk population. This project is proposed in direct response to PA-11-158: Biomarkers of Infection-Associated Cancers (R01), for which applicants were invited to investigate the association of H. pylori and gastric cancer to identify subpopulations of exposed individuals who are likely to develop cancer. Should we ascertain and validate a risk prediction model that predicts increased risk in high-incidence populations, we will create the opportunity to substantially increase prevention of this deadly cancer through targeted prevention strategies among H. pylori-infected individuals at highest risk, while also reducing unnecessary antibiotic use among those at low risk.