Comprehensive Evaluation of Lipids, Lipoproteins, and Metabolites Associated with Gastrointestinal Cancer Risk

Abstract Background: Emerging evidence indicates that lipid metabolism plays a crucial role in gastrointestinal (GI) cancers. Methods: This prospective cohort study included 112,655 cancer-free adults from UK Biobank with metabolomics data at baseline. Multivariate Cox proportional hazards regression models were employed to evaluate the associations between metabolites and GI cancers. LASSO regression was used to create metabolite risk scores, and their predictive performance for GI cancers was assessed using the C-statistic derived from the time-dependent receiver operating characteristic (ROC) curves. Results: A total of 93, 95, 33, 97, 129, and 29 metabolites were associated with colorectal, pancreatic, esophageal, gastric, hepatocellular, and gallbladder/biliary tract cancers, respectively. Higher levels of phospholipids to total lipids in large HDL% and monounsaturated fatty acids to total fatty acids percentage were associated with increased risk of all GI cancers (hazard ratios [HRs] from 1.09 to 1.34). Conversely, higher levels of unsaturated fatty acids, polyunsaturated fatty acids, ratio of polyunsaturated to monounsaturated fatty acids, and docosahexaenoic acid were associated with lower risk of six GI cancers (HRs from 0.69 to 0.93). The highest tertile of metabolic risk scores were positively associated with all GI cancers (HRs from 1.86 to 6.42), and new prediction models showed moderate accuracy for five-year cancer incidence (C-statistics from 0.713 to 0.793). Conclusions: Our findings highlight the significant role of lipid metabolism in GI cancers and provide potential noninvasive biomarkers for enhancing precise prevention. Impact: Lipid metabolism holds clinical potential for precise prevention and early intervention of gastrointestinal cancers.