Abstract 2486: Global metabolic profiling identifies novel serum markers for esophageal adenocarcinoma

Abstract

Abstract The identification of blood-based, minimally invasive markers for the early detection and diagnosis of EAC has great potential to reduce esophageal adenocarcinoma (EAC) mortality. In this context, serum metabolites are emerging as promising biomarkers for early detection of different cancer types including EAC. We used Metabolon to perform global metabolomic profiling on serum samples from two EAC case-controls studies, each consisting of 30 pairs of cases and controls. For validation, we measured two of the top consistent differentially expressed metabolites in 321 EAC cases and 331 controls. 437 metabolites were detected in discovery phase. Sixty-four metabolites had consistent differential levels between cases and controls in both batches (P<0.05).We selected two metabolites (one amino acid and one keytone) for validation. Consistent with the discovery phase, cases had lower levels of the specific amino acid (mean ± SD; 22.78 ±6.79 mg/ml vs 28.24±8.64 mg/ml; P<0.001) and higher levels of the specific keytone (18.80±19.26 mg/ml vs 7.98 ±10.86mg/ml; P<0.001) than controls. Using the median value as a cut-off point, higher levels of the amino acid were associated with significant decreased risk of EAC (OR=0.30: 95% confidence interval (CI), 0.21-0.42; p<0.001). However, a significant increased risk of EAC was associated with higher levels of the keytone with OR of 3.71 (2.59-5.32). Quartile analyses showed a dose-response relationship between these two metabolites and EAC risk. Using the lowest quartile as reference, ORs for the 2nd, 3th and 4th quartiles were 0.40 (0.26-0.62), 0.27(0.17-0.43) and 0.14 (0.08-0.24) (P for trend < 0.001) for the amino acid; and 2.43 (1.31-4.51), 3.28 (1.80-5.97) and 9.55 (5.40-16.89) (P for trend < 0.001) for the keytone. A significant joint effect between low amino acid levels and high keytone levels on EAC risk was seen: subjects with one risk factor had an increased risk of 1.33 (0.74-2.38) to 1.51 (0.84-2.70) and subjects with both risk factors had an increased risk of 6.59 (4.03-10.78) (P interaction = 0.002). A joint effect between low amino acid levels and smoking was also seen, with ORs of 4.47 (2-33-8.59) to 5.49 (2.88-10.44) for subjects with one risk factor and 11.38 (6.18-20.94) for subjects with both risk factors, with a borderline significant interaction (P=0.051). A similar joint effect was seen for high keytone levels and smoking with ORs of 2.94 (1.56-5.55) to 3.79 (2.03-7.06) for subjects with one risk factor and 10.50 (5.78-19.08) for subjects with both risk factors. Metabolite Set Enrichment Analyses (MSEA) pointed to alterations in protein biosynthesis, fatty acids, energy and bile acid metabolism as key metabolic pathways related to EAC development. In conclusions, we identified two metabolites that have the potential to become novel biomarkers for early detection of EAC. Citation Format: Beatriz Sanchez-Espiridion, Dong Liang, Jaffer A. Ajani, Su Liang, Yuanqing Ye, Michelle AT Hildebrandt, Jian Gu, Xifeng Wu. Global metabolic profiling identifies novel serum markers for esophageal adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2486. doi:10.1158/1538-7445.AM2014-2486