The prevalence of colorectal cancer (CRC) continues to increase worldwide and it remains the third most
commonly diagnosed cancer in the United States. An enhanced understanding of CRC etiology is essential to
develop tailored risk prediction methods. Metabolomics, the comprehensive study of small metabolites, is a
promising approach to discover etiological biomarkers for CRC. Metabolomics analysis in combination with
information on dietary intake could be used for the identification of objective dietary biomarkers for CRC.
However, precise metabolic biomarkers to predict CRC are missing. To date, there are no objective dietary
biomarkers for CRC risk and the biology underlying the relationship between diet and CRC remains poorly
The goal of the proposed work is to investigate associations of metabolites with CRC risk and to enhance
our understanding of the underlying biology of the diet-CRC relationship. To achieve this goal, we will use
existing global metabolomics data generated in three state-of-the art laboratories using pre-diagnosis
biospecimens from eight independent, prospective cohorts from the US, Europe, and Asia. These well-
annotated and unique datasets include data from n=3,085 matched case-control pairs from diverse
populations, and thus ensure broad generalizability and clinical applicability of identified biomarkers. Data are
integrated in the NIH-funded Consortium of Metabolomics Studies (COMETS) together with standardized and
validated food frequency questionnaires (FFQ), and epidemiologic and clinical data. We will discover and
validate novel blood-based metabolic biomarkers for CRC risk (Aim 1) in a discovery set of n=1,900
matched case-control pairs. Findings will be confirmed in an independent validation set including n=1,185
matched case-control pairs. Additionally, we will perform stratified analyses by sex, tumor location, and age at
diagnosis to advance our understanding of CRC etiology across distinct subtypes. Using the described
datasets, we will discover and validate correlations of food groups with metabolites. We will perform
mediation analysis for the top performing diet-metabolite correlations to investigate the indirect effect
of diet on CRC risk through metabolites (Aim 2). The proposed research is highly innovative in that it uses
a rigorous multi-step design, employs for the first time a broad set of metabolic biomarkers (n~381) and dietary
information, from highly characterized cohorts with biospecimens and questionnaires collected before cancer
diagnosis, thus, protecting against reverse causation. Our interdisciplinary team has extensive experience in
using metabolomics in cancer research and leverages substantial preliminary data. We expect that our
investigation will discover and validate novel CRC biomarkers and enhance our understanding of the
underlying biology of diet in CRC etiology, thus addressing a clearly defined clinical and public health need.
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