Plasma Metabolomics Reveals Diagnostic Biomarkers and Risk Factors for Esophageal Squamous Cell Carcinoma

Esophageal squamous carcinoma (ESCC) has a high morbidity and mortality rate. Identifying risk metabolites associated with its progression is essential for the early prevention and treatment of ESCC. A total of 373 ESCC, 40 esophageal squamous dysplasia (ESD), and 218 healthy controls (HC) subjects were enrolled in this study. Gas chromatography-mass spectrometry (GC/MS) was used to acquire plasma metabolic profiles. Receiver operating characteristic curve (ROC) and adjusted odds ratio (OR) were calculated to evaluate the potential diagnosis and prediction ability markers. The levels of alpha-tocopherol and cysteine were progressively decreased, while the levels of aminomalonic acid were progressively increased during the various stages (from precancerous lesions to advanced-stage) of exacerbation in ESCC patients. Alpha-tocopherol performed well for the differential diagnosis of HC and ESD/ESCC (AUROC>0.90). OR calculations showed that a high level of aminomalonic acid was not only a risk factor for further development of ESD to ESCC (OR>13.0) but also a risk factor for lymphatic metastasis in ESCC patients (OR>3.0). A low level of alpha-tocopherol was a distinguished independent risk factor of ESCC (OR< 0.5). The panel constructed by glycolic acid, oxalic acid, glyceric acid, malate and alpha-tocopherol performed well in distinguishing between ESD/ESCC from HC in the training and validation set (AUROC>0.95). In conclusion, the oxidative stress function was impaired in ESCC patients, and improving the body's antioxidant function may help reduce the early occurrence of ESCC.