Abstract
AIMS/HYPOTHESIS: Type 2 diabetes has been associated with increased risk of colorectal cancer (CRC), but the specific diabetogenic pathways contributing to this risk remain unclear. METHODS: We analysed individual-level data from 129,420 participants of European ancestry in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR), comprising 58,531 patients with CRC and 70,889 control participants. We applied eight validated partitioned polygenic scores (PPSs) representing distinct diabetogenic processes: two related to relative insulin secretion insufficiency and six to insulin resistance with varying degrees of preserved insulin secretion. Adjusted ORs and 95% CIs for CRC and early-onset CRC were estimated using conditional logistic regression. RESULTS: PPSs reflecting insulin resistance-linked hyperinsulinaemia, particularly those related to lipodystrophy, body fat and obesity, were associated with higher odds of CRC (p<0.001 for each). Compared with individuals in the lowest decile, those in the highest decile had ORs of 1.09 (95% CI 1.05, 1.14), 1.13 (1.09, 1.18) and 1.15 (1.10, 1.20) for lipodystrophy, body fat and obesity, respectively. In contrast, PPSs for insulin secretion insufficiency or insulin resistance without hyperinsulinaemia were not associated with CRC. The obesity-related hyperinsulinaemic insulin resistance PPS was also associated with higher odds of early-onset CRC (OR for top vs bottom decile=1.26; 95% CI 1.13, 1.41), with the strongest association among those with obesity (OR 1.75; 95% CI 1.46, 2.11; p value for interaction with BMI <0.001). CONCLUSIONS/INTERPRETATION: Diabetogenic processes characterised by insulin resistance-linked hyperinsulinaemia were associated with increased odds of CRC, including early-onset disease. These findings offer new insights into diabetes-CRC pathogenesis, and may inform targeted prevention strategies.