Metabolomic profiling and colorectal cancer risk

Dr Marc Gunter’s study provides new insights into metabolic pathways that may play a role in colon cancer development

  • Topic: Colorectal cancer
  • Institution: Imperial College London
  • Country: United Kingdom
  • Status: Completed
Researcher: Marc Gunter


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. Metabolomics is a powerful, high-throughput approach to identifying metabolic signatures that are associated with disease development, and can simultaneously measure several hundred small molecules that are the products of human metabolism. 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. However, we do not yet understand which specific metabolic pathways are relevant to colorectal cancer.

Hypothesis and objectives

  1. To investigate the association of metabolite profiles with colorectal cancer risk using multivariate modeling techniques.
  2. To assess the relationship between metabolite profiles and colorectal cancer risk factors including anthropometric and metabolic parameters, diet, endogenous hormone levels and genetic variants.
  3. To explore the extent to which the associations of colorectal cancer with its risk factors are mediated by specific metabolites.

We hypothesised that there are specific metabolite profiles that are intermediary parameters, and accounting for them will explain the association between colorectal cancer and its risk factors.

How the study was carried out

A nested case-control study of metabolomic profiling and colorectal cancer was conducted in a sample of 500 incident colorectal cancers and 500 controls among EPIC participants. Pre-diagnostic plasma specimens underwent metabolomic profiling using state-of-the-art mass spectrometry and chromatography techniques that accurately quantified levels of ~250 key metabolites including detailed characterisation of phospholipids. Multivariate regression modelling techniques with control for multiple comparisons and established colorectal cancer risk factors, including endogenous hormone levels, were conducted.


In total, 26 metabolites were associated with risk of colon cancer, but due to the many statistical tests performed we had to apply a more stringent cut-off level for significance. Histidine was the only metabolite to remain significantly associated with colon cancer risk following the application of the stringent significance cut-off. Individuals in the highest quartile of histidine levels had a near 50% reduced risk of colon cancer compared with individuals in the lowest quartile (Q4 vs. Q1 OR= 0.47, 95% CI 0.31-0.71, p-trend<0.001). The amino acid histidine can be converted into histamine by the gut microbiota. Histamine has an important role in the inflammatory response but its specific role in colon cancer development is thus far unknown.

This study provides new insights into metabolic pathways that may play a role in colon cancer development and highlights a possible role for histidine metabolism in the development of this cancer.

Grant publications