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Metabolomics is a powerful, high-throughput approach to identifying metabolic signatures that are associated with disease development and several recent studies have leveraged metabolite profiling to provide new insights into disease processes such as heart disease and diabetes mellitus (Wang et al., Nat Med; 17(4):448–453). The detailed assessment of biochemical pathways and novel metabolic intermediates may provide important new insights into the mechanisms of colorectal tumorigenesis with additional broader implications for other malignancies. As an initial step, we recently profiled a limited panel of metabolites in 180 incident colorectal cancer cases and 180 matched-controls from a sub-cohort within the European Prospective Investigation into Cancer and Nutrition (EPIC). In a multivariate model that included colorectal cancer risk factors, we observed statistically significant associations between colorectal cancer risk and levels of several long-chain phospholipids (all P<10-4). These findings provide preliminary evidence that there are significant differences in levels of specific phospholipids between colorectal cancer cases and controls that may be suggestive of novel biochemical pathways associated with colorectal tumorigenesis. However, to verify and characterize the observed associations between these metabolites and colorectal cancer development, a more rigorous evaluation is necessary with detailed profiling of metabolites in an independent population of appropriate sample size to control for multiple comparisons and established colorectal cancer risk factors.
A nested case-control study of metabolomic profiling and colorectal cancer will be conducted in a sample of 500 incident colorectal cancers and 500 controls among EPIC participants, independent of those included in our pilot analysis. Pre-diagnostic plasma specimens will undergo metabolomic profiling using state-of-the-art mass spectrometry and chromatography techniques that can accurately quantify levels of ~250 key metabolites including detailed characterization of phospholipids. Multivariate regression modeling techniques with control for multiple comparisons and established colorectal cancer risk factors, including endogenous hormone levels, will be conducted.
Colorectal cancer is the most third common malignancy worldwide with more than 1.2 million new cases diagnosed each year. The observed relationships with obesity and metabolic syndrome suggest that metabolic dysfunction plays a significant role in colorectal cancer but the underlying biological mechanisms are not fully understood. The application of detailed metabolite profiling within the context of a prospective cohort study has the potential to identify novel metabolites and biochemical pathways associated with colorectal cancer development with important implications for risk prediction and novel prevention strategies.
The risk of developing colorectal cancer is increased in individuals who are overweight and diabetic, suggesting that metabolic abnormalities may play a role in colorectal cancer development. However, we do not understand which specific metabolic pathways are relevant to colorectal cancer.
We propose to perform a detailed analysis of the metabolic pathways that are associated with colorectal cancer development by using a newly developed technology, termed metabolomics. Metabolomics can simultaneously measure several hundred small molecules that are the products of human metabolism.
We will use metabolomics to investigate metabolic pathways in individuals enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC), a study of >500,000 men and women living in 10 European Countries who provided a blood sample and detailed information on diet and lifestyle at enrolment. We will measure metabolite levels in 500 individuals who developed colorectal cancer and compare levels to 500 participants who did not develop cancer.
The proposed study is one of the first of its kind and has the potential to identify new metabolic processes that lead to colorectal cancer. This will improve our understanding of how an individual's metabolism can affect risk of colorectal cancer development and may allow identification of those at highest risk of developing this common disease.