Data are shown as medians and interquartile range (IQR) or n and the percentage. P values were computed using χ² tests for categorical variables or two-sided Kruskal-Wallis tests for continuous variables. CD4, CD4 T cells; CD8, CD8 T cells; WBCs, white blood cells. a P value on clinical grade was based on comparison among symptomatic S2, S3 and convalescent S4 patients excluding S1. Clinical grade classification was infeasible for presymtomatic S1 patients who did not exhibit any clinical symptoms at the time of blood collection.

IMPORTANCE Metabolic deregulation plays an important role in gastric cancer (GC) development.To date, no studies have comprehensively explored the metabolomic profiles along the cascade of gastric lesions toward GC.OBJECTIVE To draw a metabolic landscape and define metabolomic signatures associated with the progression of gastric lesions and risk of early GC. DESIGN, SETTING, AND PARTICIPANTSA 2-stage, population-based cohort study was initiated in 2017 in Linqu County, Shandong Province, China, a high-risk area for GC. Prospective follow-up was conducted during the validation stage (June 20, 2017, to May 27, 2020). A total of 400 individuals were included based on the National Upper Gastrointestinal Cancer Early Detection Program in China. The discovery stage involved 200 individuals with different gastric lesions or GC (high-grade intraepithelial neoplasia or invasive GC). The validation stage prospectively enrolled 152 individuals with gastric lesions who were followed up for 118 to 1063 days and 48 individuals with GC. EXPOSURES Metabolomic profiles and metabolite signatures were examined based on untargeted plasma metabolomics assay. MAIN OUTCOMES AND MEASURESThe risk of GC overall and early GC (high-grade intraepithelial neoplasia), and progression of gastric lesions. RESULTSOf the 400 participants, 124 of 200 (62.0%) in the discovery set were men; mean (SD) age was 56.8 (7.5) years. In the validation set, 136 of 200 (68.0%) were men; mean (SD) age was 57.5 (8.1) years. Distinct metabolomic profiles were noted for gastric lesions and GC. Six metabolites, including α-linolenic acid, linoleic acid, palmitic acid, arachidonic acid, sn-1 lysophosphatidylcholine (LysoPC)(18:3), and sn-2 LysoPC(20:3) were significantly inversely associated with risk of GC overall and early GC (high-grade intraepithelial neoplasia). Among these metabolites, the first 3 were significantly inversely associated with gastric lesion progression, especially for the progression of