Development and Validation of a High-Throughput Mass Spectrometry Based Urine Metabolomic Test for the Detection of Colonic Adenomatous Polyps.

Background: Colorectal cancer is one of the leading causes of cancer deaths worldwide. The detection and removal of the precursors to colorectal cancer, adenomatous polyps, is the key for screening. The aim of this study was to develop a clinically scalable (high throughput, low cost, and high sensitivity) mass spectrometry (MS)-based urine metabolomic test for the detection of adenomatous polyps. Methods: Prospective urine and stool samples were collected from 685 participants enrolled in a colorectal cancer screening program to undergo colonoscopy examination. Statistical analysis was performed on 69 urine metabolites measured by one-dimensional nuclear magnetic resonance spectroscopy to identify key metabolites. A targeted MS assay was then developed to quantify the key metabolites in urine. A MS-based urine metabolomic diagnostic test for adenomatous polyps was established using 67% samples (un-blinded training set) and validated using the remaining 33% samples (blinded testing set). Results: The MS-based urine metabolomic test identifies patients with colonic adenomatous polyps with an AUC of 0.692, outperforming the NMR based predictor with an AUC of 0.670. Conclusion: Here we describe a clinically scalable MS-based urine metabolomic test that identifies patients with adenomatous polyps at a higher level of sensitivity (86%) over current fecal-based tests (<18%).

Clinical validation of a novel urine-based metabolomic test for the detection of colonic polyps on Chinese population.

PURPOSE: Colorectal cancer is the fifth leading cause of cancer-related deaths in China. When detected early, with the removal of adenomatous polyps, precursors of colorectal cancer, it is preventable. The aim of this study was to evaluate a novel urine-based metabolomic diagnostic test for the detection of adenomatous polyps, PolypDx™, that was originally developed and validated using 1000 samples from Canadian Cohort, on Chinese population. METHODS: Prospective urine samples were collected from 1000 participants undergoing colonoscopy examination, from March 2013 to July 2014 at Minhang District, Shanghai Centre for Disease Control and Prevention. One-dimensional nuclear magnetic resonance spectra of urine metabolites were analyzed to determine the concentrations of three key metabolites used in PolypDx™. The predicted results were then compared to the gold standard for colorectal cancer diagnostic, colonoscopy. Area under curve (AUC) was calculated specifically for the Chinese population and compared with the Canadian dataset. Sensitivity and specificity of this urine-based metabolomic diagnostic test were also compared with three commercially available fecal-based tests. RESULTS: An AUC of 0.717 for PolypDx™ was calculated on Chinese dataset which is slightly lower than the AUC on the Canadian dataset. A sensitivity of 82.6% and a specificity of 42.4% were achieved on Chinese dataset. CONCLUSIONS: Here, we validated a novel urine-based metabolomic diagnostic test for the detection of adenomatous polyps, PolypDx™, on Chinese population through a sample size of 1000 participants with a greater level of sensitivity than fecal-based tests.

Metabolomic profiles are gender, disease and time specific in the interleukin-10 gene-deficient mouse model of inflammatory bowel disease.

Metabolomic profiling can be used to study disease-induced changes in inflammatory bowel diseases (IBD). The aim of this study was to investigate the difference in the metabolomic profile of males and females as they developed IBD. Using the IL-10 gene-deficient mouse model of IBD and wild-type mice, urine at age 4, 6, 8, 12, 16, and 20 weeks was collected and analyzed by nuclear magnetic resonance (NMR) spectroscopy. Multivariate data analysis was employed to assess differences in metabolomic profiles that occurred as a consequence of IBD development and severity (at week 20). These changes were contrasted to those that occurred as a consequence of gender. Our results demonstrate that both IL-10 gene-deficient and wild-type mice exhibit gender-related changes in urinary metabolomic profile over time. Some male-female separating metabolites are common to both IL-10 gene-deficient and control wild-type mice and, therefore, appear to be related predominantly to gender maturation. In addition, we were able to identify gender-separating metabolites that are unique for IL-10 gene-deficient and wild-type mice and, therefore, may be indicative of a gender-specific involvement in the development and severity of the intestinal inflammation. The comparison of the gender-separating metabolomic profile from IL-10 gene-deficient mice and wild-type mice during the development of IBD allowed us to identify changes in profile patterns that appear to be imperative in the development of intestinal inflammation, but yet central to gender-related differences in IBD development. The knowledge of metabolomic profile differences by gender and by disease severity has potential clinical implications in the design of both biomarkers of disease as well as the development of optimal therapies.

Metabolomics and detection of colorectal cancer in humans: a systematic review.

Metabolomics represents one of the new omics sciences and capitalizes on the unique presence and concentration of small molecules in tissues and body fluids to construct a 'fingerprint' that can be unique to the individual and, within that individual, unique to environmental influences, including health and disease states. As such, metabolomics has the potential to serve an important role in diagnosis and management of human conditions. Colorectal cancer is a major public health concern. Current population-based screening methods are suboptimal and whether metabolomics could represent a new tool of screening is under investigation. The purpose of this systematic review is to summarize existing literature on metabolomics and colorectal cancer, in terms of diagnostic accuracies and distinguishing metabolites. Eight studies are included. A total of 12 metabolites (taurine, lactate, choline, inositol, glycine, phosphocholine, proline, phenylalanine, alanine, threonine, valine and leucine) were found to be more prevalent in colorectal cancer and glucose was found to be in higher proportion in control specimens using tissue metabolomics. Serum and urine metabolomics identified several other differential metabolites between controls and colorectal cancer patients. This article highlights the novelty of the field of metabolomics in colorectal oncology.