Identification of Serum Markers of Esophageal Adenocarcinoma by Global and Targeted Metabolic Profiling

Abstract

Background & aims: We aimed to identify new serum biomarkers of esophageal adenocarcinoma (EAC).

Methods: We performed metabolomic analyses of serum samples from 2 sets of case-control pairs in the discovery phase, each consisting of 30 patients with histologically confirmed EAC (cases) from the University of Texas MD Anderson Cancer Center and 30 matched subjects without EAC (controls). We identified metabolites whose levels differed significantly between cases and controls and validated those with the greatest difference in an analysis of 321 EAC cases and 331 controls. We generated a metabolite risk score (MRS) for the metabolites.

Results: The levels of 64 metabolites differed significantly between EAC cases and controls in the discovery phase. The metabolites with the greatest difference were amino acid L-proline (LP), ketone body 3-hydroxybutyrate (BHBA), and carbohydrate D-mannose (DM); these differences were confirmed in the validation set. Cases had lower mean levels of LP than controls (22.78 ± 6.79 μg/mL vs 28.24 ± 8.64 μg/mL; P < .001) and higher levels of BHBA (18.06 ± 17.84 μg/mL vs 7.73 ± 9.92 μg/mL; P < .001) and DM (9.87 ± 4.28 μg/mL vs 6.28 ± 3.61 μg/mL; P < .001). Levels of DM were significantly higher in patients with late-stage EAC than early-stage EAC (10.61 ± 4.79 μg/mL vs 8.97 ± 3.36 μg/mL; P = .005). Higher levels of LP were associated with significant decrease in risk of EAC (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.18-0.38). A significant increase in risk of EAC was associated with higher levels of BHBA (OR, 4.05; 95% CI, 2.84-5.78) and DM (OR, 7.04; 95% CI, 4.79-10.34). Levels of all 3 metabolites associated with EAC risk in a dose response manner; the level of risk conferred by the metabolites increased jointly with smoking status and body mass index. Individuals with high MRS had significant (7.76-fold) increase in risk of EAC vs those with low MRS. Smokers with high MRS had the greatest risk of EAC (OR, 23.40; 95% CI, 10.95-50.00), compared with never smokers with low MRS.

Conclusions: On the basis of a case vs control metabolic profile analysis, levels of LP, BHBA, and DM are associated with risk of EAC. These markers might be used as risk and prognostic factors for patients with EAC.

Keywords: Esophageal Cancer; Metabolomics; Serum Biomarkers.