Circulating metabolites as novel risk biomarkers for gastric cancer: a large multi-center prospective investigation - ABSTRACT Gastric cancer is one of the most common and deadly cancers globally, accounting for over one million new cancer diagnoses and 783,000 deaths in 2018. Infection of Helicobacter pylori (H. pylori) is the most important risk factor and a necessary cause for non-cardia gastric cancer. While targeting high-risk populations who are infected with H. pylori seems a compelling strategy for gastric cancer screening and prevention, a significant concern not addressed is that only ~1 to 3% of the H. pylori infected individuals develop gastric cancer, indicating that a strategy based on H. pylori status alone is insufficient, particularly among populations with a relatively low prevalence of H. pylori infection. Thus, discovering and validating additional biomarkers, especially non-invasive ones, is necessary to facilitate the development of novel risk assessment tools for gastric cancer. The human metabolome reflects endogenous responses to exposures, including environmental and lifestyle factors that are related to carcinogenesis. The use of advanced metabolomics techniques in prospective population -based cohort studies has successfully identified both novel etiologic factors and risk biomarkers for different cancers. However, few prior studies have focused on identifying novel risk biomarkers for gastric cancer using metabolomics techniques, particularly in prospective design settings. We recently conducted the first nested case-control study within two large prospective cohorts. Our study identified 5 metabolites associated with risk of gastric cancer after correction for multiple comparisons, and 13 additional metabolite candidates for further investigations. These include metabolites related to vitamin B12 deficiency, green tea/coffee intake, and two progestin steroids, representing a few biologically plausible mechanisms involved in gastric cancer etiology. Herein, we propose to conduct a large prospective investigation within a newly formed international consortium to validate these highly promising findings, as well as discovering novel risk biomarkers, using both untargeted and targeted metabolomics approaches. Pre-diagnostic plasma samples and epidemiologic data including demographics, lifestyle factors, and dietary intakes will be harmonized for ~1,200 incident cases and 1,600 matched controls from six prospective cohorts. The proposed study will incorporate a rigorous two-stage design to screen and validate circulating metabolite biomarkers for gastric cancer risk in East Asians and European Whites (Aim 1 & 2). Furthermore, we will assess mediating effects of the identified metabolites on the associations between known risk factors and gastric cancer to facilitate the understanding of involved biological mechanisms (Aim 3). Through aseries of rigorously designedresearch activities, fresh insights into mechanisms of gastric carcinogenesis and novel biomarkers for future development of risk assessment tools are expected.
