Metabolomic profiles througout the continuum of colorectal carcinogenesis (MetaboCCC)

Metabolomics is an innovative and powerful approach by which a large number of metabolites are systematically screened to characterize biological phenotypes with an unprecedented level of precision. New biomarkers that help characterize risk of progression along the pathway of colorectal carcinogenesis are urgently needed to tailor prevention strategies. By investigating plasma from individuals free of colorectal tumors, patients with colorectal adenoma, and patients with colorectal cancer (CRC, stage I-IV), the newly formed CRC-Metabol Consortium aims to investigate changes in the metabolome along the continuum of colorectal carcinogenesis. We will perform metabolomic analyses in 2,300 plasma samples derived from well-defined populations of four TRANSCAN countries (the Netherlands, Germany, Austria, Norway) with assays completed at an expert site (France), using multiple discovery and replication sets to define biologic mechanisms of colorectal carcinogenesis. Austria will contribute with plasma from 400 CRC cases, 400 adenoma and 400 controls to the proposed study. For a comprehensive and complementary strategy, we will apply both targeted and untargeted metabolomics. The proposed CRC-Metabol consortium will use cutting-edge detection technologies such as ultra-pressure liquid chromatography (UPLC)- quadruple time of flight (qTOF) and UPLC-tandem mass spectrometry (QTRAP) and a study-design with multiple discovery phases and internal and external validation phases. The data management will be take place in Austria. There the data will be harmonized and pooled into a central database. The main part of the statistical analyses will be performed in Austria. We aim to a) determine preventive or predisposing plasma metabolites discerning adenoma cases from controls, b) determine plasma metabolites that characterize CRC, and are distinct from controls or adenoma cases, and c) test for markers that discern CRC stages. We expect that the discovery of novel metabolites in blood that define the transition between various stages of colorectal carcinogenesis can be used in the future for risk stratification, including tailored prevention strategies by endoscopy.

Despite advances in the diagnosis and treatment of human malignancy, cancer remains a major public health problem and among the leading causes of morbidity and mortality worldwide. Colorectal cancer presents the third most common cancer in men and the second most common cancer in women in the EU and has a natural history of evolution from normal mucosa to adenoma to cancer. This process spans on average 1020 years, thereby providing a window of opportunity for effective intervention and prevention. Thus, the discovery of biomarkers that aid in the characterization of risk of colorectal cancer development are urgently needed to tailor effective prevention strategies. Metabolomics, a new approach, by which a large number of metabolites are systematically screened, is being increasingly applied as the method of choice for biomarker discovery. Within the MetaboCCC project we conducted a metabolomics study of more than 2,000 colorectal cancer patients, patients with adenomas, and disease-free individuals. This study aims to determine plasma metabolites that characterize colorectal cancer and test for markers that differentiate different stages of colorectal cancer. The MetaboCCC project involved five patient cohorts from four different European countries, the Netherlands, Germany, Austria and Norway. Within a first analysis, we identified 28 metabolites that were associated with colorectal cancer. These results were verified in a discovery-validation approach by using two datasets from two study cohorts. In addition, a comprehensive data pre-processing strategy, allowing the analysis of big datasets from multi-cohort projects, has been developed. Our study reports promising metabolites associated with colorectal cancer and elucidates the potential of metabolomic markers to complement current screening strategies.