Abstract
BACKGROUND: Patients with colorectal adenoma polyps (PLPs) are at higher risk for developing colorectal cancer (CRC). However, the development of improved and robust biomarkers to enable the screening, surveillance, and early detection of PLPs and CRC continues to be a challenge. The aim of this study was to identify biomarkers of progression to CRC through metabolomic profiling of human serum samples with a multistage approach. METHODS: Metabolomic profiling was conducted with the Metabolon platform for 30 CRC patients, 30 PLP patients, and 30 control subjects, and this was followed by the targeted validation of the top metabolites in an additional set of 50 CRC patients, 50 PLP patients, and 50 controls with liquid chromatography-tandem mass spectrometry. Unconditional multivariate logistic regression models, adjusted for covariates, were used to evaluate associations with PLP and CRC risk. RESULTS: For the discovery phase, 404 serum metabolites were detected, with 50 metabolites showing differential levels between CRC patients, PLP patients, and controls (P for trend < .05). After validation, the 3 top metabolites (xanthine, hypoxanthine, and d-mannose) were validated: lower levels of xanthine and hypoxanthine and higher levels of d-mannose were found in PLP and CRC cases versus controls. A further exploratory analysis of metabolic pathways revealed key roles for the urea cycle and caffeine metabolism associated with PLP and CRC risk. In addition, a joint effect of the top metabolites with smoking and a significant interaction with the body mass index were observed. An analysis of the ratio of hypoxanthine levels to xanthine levels indicated an association with CRC progression. CONCLUSIONS: These results suggest the potential utility of circulating metabolites as novel biomarkers for the early detection of CRC. Cancer 2017;123:4066-74. © 2017 American Cancer Society.