Abstract 8: Global and targeted metabolomic profiling of colorectal cancer progression

Abstract

Abstract Background: Colorectal cancer (CRC) is one of the most prevalent and deadly cancers in the world. The development of improved and robust biomarkers to enable screening, surveillance, and early detection of CRC continues to be a challenge. Patients with colorectal adenoma are at higher risk of developing colon cancer; however, noninvasive methods to identify these patients are still on demand. The aim of this study was to identify biomarkers of CRC disease progression by using metabolomic profiling of human serum samples in a multistep approach. Methods: We performed global metabolomic profiling on 30 human serum samples from patients with colorectal adenoma, 30 CRC patients and 30 healthy controls who were matched by age, gender and ethnicity. For validation, we measured the three top differentially expressed metabolites in an additional set of 50 adenoma, 50 CRC and 50 healthy controls. Results: Global biochemical profiles of 404 metabolites were detected, with 301 metabolites remaining after quality control procedures. In discovery phase, 50 metabolites had differential levels between colorectal adenoma, CRC and controls (P for trend <0.05), with 19 metabolites showing increased levels in CRC and adenoma in comparison to controls and 31 metabolites with decreased levels. Further exploratory analyses of these metabolites showed a key role for metabolic pathways involving urea cycle, caffeine and galactose metabolism as associated with CRC progression. The top 3 differentially expressed metabolites (Xanthine, Hypoxanthine and D-mannose) were selected for validation. Consistent with the discovery phase, CRC cases and adenoma had lower levels of Xanthine than controls (mean ± SD; 9.95 ±0.92 mg/ml vs 10.63±0.97 mg/ml; P<0.001 and 9.87±0.75 vs 10.63±0.97 mg/ml; P<0.001). The same trend was observed for Hypoxanthine (mean ± SD; 10.72 ±0.62 mg/ml vs 12.29±1.60; P<0.001 and 10.71±0.61 vs 12.29±1.60 mg/ml; P <0.001) whereas higher levels of D-mannose where observed in both CRC cases and adenoma when compared to controls (3.32±0.58 mg/ml vs 2.32 ±0.90mg/ml; P<0.001 and 3.32±0.58 mg/ml vs 2.32 ±0.90mg/ml; P<0.001). Using the median value of controls as a cut-off point, 94% of the adenoma and CRC cases showed low levels of Xanthine (Odds Ratio (OR) = 10.47, 95% confidence interval (CI) = 2.63-41.63 for adenoma; OR = 38.76 and 95% CI = 6.58-228.51 for CRC). For Hypoxanthine, 90% of the adenoma and CRC cases showed low levels (OR = 6.50 and 95% CI = 1.98–21.24 for adenoma; OR = 11.19 and 95% CI = 3.28-38.21 for CRC). For D-Mannose, all adenoma cases had high levels (OR is not available due to 0 count) and 92% of CRC cases (OR = 15.99, 95% Ci = 4.07-62.88, P< 0.001) had high levels of D-Mannose, compared to 50% of controls having high levels of D-Mannose. Conclusions: Our results suggest the potential utility of the identified metabolites as new valuable biomarkers for early detection of CRC. Citation Format: Beatriz Sanchez-Espiridion, Lindsey White, Lopa Mishra, Gottumukkala S. Raju, Scott Kopetz, Jian Gu, Yuanquing Ye, Xifeng Wu, Dong Liang. Global and targeted metabolomic profiling of colorectal cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 8.