Abstract 2316: Circulating lipid and bile acid metabolites as predictors of colorectal cancer risk: A multi-cohort metabolomics meta-analysis

Abstract Background: Metabolic dysregulation has been implicated in colorectal cancer (CRC) development but not fully characterized. We conducted a large-scale metabolomics meta-analysis to identify circulating metabolites associated with future CRC risk across heterogeneous populations. Methods: We harmonized pre-diagnostic metabolomic and covariate data from seven prospective cohorts: the Cancer Prevention Study II Nutrition Cohort (CPS-II), the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), the Women’s Health Initiative Metabolomics in Nutrition Study (WoMIN), the Nurses’ Health Study (NHS), the Health Professionals Follow-up Study (HPFS), the Shanghai Women’s Health Study (SWHS), and the Shanghai Men’s Health Study (SMHS). Using multivariable logistic regression, we applied fixed-effects meta-analysis to evaluate associations between 1,039 harmonized metabolites and CRC risk, adjusting for body mass index and other covariates. Results: Across seven cohorts (N = 3,779, 50% cases), participants were predominantly female (59.5%), with a median age of 68 years (IQR 62-73) and median BMI of 25.0 kg/m2 (IQR 23.0-28.0). Fourteen metabolites were significantly associated with CRC risk (FDR < 0.05). Inverse associations were observed for phospholipids and ether lipids enriched in polyunsaturated fatty acids (e.g., PE(20:0/18:2), PE(22:6/P-18:1), PC(22:6/18:0); OR range 0.47-0.63, p-value range 6.2E-04 to 6.8E-13). Positive associations included monoacylglycerols (MG(18:3)), bile acids (e.g., glycochenodeoxycholate), and xenobiotic compounds (e.g., N-undecylbenzenesulfonic acid). Heterogeneity was low (mean I2 across the significant metabolites was ∼ 15%), and directionality was consistent across studies. Conclusions: This multi-cohort analysis identified lipid metabolism and bile acid signaling as key pathways in CRC etiology, among others, independent of adiposity. The inverse associations with polyunsaturated lipid species and the positive association with bile acids and xenobiotics suggest that membrane lipid remodeling, gut-liver axis perturbations, and environmental exposures may play mechanistic roles in CRC development. Ongoing external validation in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort using untargeted metabolomic data will inform the utility of these metabolites as biomarkers for CRC risk stratification and prevention. Citation Format: Mary Playdon, Emma Braun, Kelly Santucci, A. Heather Eliassen, Edward L. Giovannucci, Marc Gunter, Steven Moore, Lorelei A. Mucci, Xiao-Ou Shu, Mingyang Song, Ying Wang, Danxia Yu, Wei Zheng, Cornelia M. Ulrich, Jennifer Ose. Circulating lipid and bile acid metabolites as predictors of colorectal cancer risk: A multi-cohort metabolomics meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2316.