Colorectal cancer is the third most common cancer globally and the second most common cause of cancer death. Obesity and Type 2 diabetes increase colorectal cancer risk and metabolic perturbations such as hyperinsulinemia and elevated insulin-like growth factor (IGF)-1 have been purported to explain these relationships. However, prospective studies that have investigated biomarkers of hyperinsulinemia and IGF-1 in relation to colorectal cancer risk have yielded inconsistent findings. In a pooled analysis of data from 12 prospective cohorts investigating these biomarkers and colorectal cancer; I identified positive associations between circulating C-peptide (odds ratio [OR]=1.12, 95% confidence interval [CI]=1.04-1.21) and IGF-1 (OR=1.14, 95% CI=1.04-1.24) with colorectal cancer.
I then investigated metabolically-characterised body size phenotypes and colorectal cancer. Overweight individuals without hyperinsulinemia (i.e. metabolically-healthy) were not at increased risk of colorectal cancer (OR=0.91, 95% CI=0.74-1.11); however, those with poor metabolic health were at elevated risk of colorectal cancer regardless of their body size, with the strongest effect detected among the metabolically-unhealthy overweight (OR=1.34, 95% CI=1.09-1.65). This supports the hypothesis that a metabolic phenotype characterised by hyperinsulinemia, which invariably is associated with obesity, though not exclusively, is positively associated with colorectal cancer.
Finally, I used a targeted metabolomic assay in a nested case-control study to identify novel metabolic markers of colon cancer. A panel of metabolites including four amino acids and six lipids was associated with colon cancer development. The strongest association was detected for the amino acid histidine (OR=0.22, 95% CI=0.10-0.46). These results point towards novel metabolic pathways that are relevant for colorectal cancer development. Given that all of the biomarkers investigated are modifiable, meaning that individuals can alter their exposures through dietary or lifestyle changes, and in some instances pharmacological interventions, the results from this thesis may offer clues for novel prevention strategies.