Consistent Metabolomic and Genetic Evidence Supports Acisoga as a Key Contributor to Colorectal Neoplasia Progression

Abstract

Background: Colorectal cancer is a leading cause of cancer incidence and mortality worldwide. Early detection and accurate risk stratification of precursor lesions remain critical challenges. Integrating metabolomics with genetic analysis may improve the understanding of colorectal cancer development and identify disease determinants.Methods: Untargeted serum metabolomics was performed in 513 individuals: 185 controls; 74 with low-, 98 with intermediate-, and 100 with high-risk lesions; and 56 colorectal cancer cases. Overall, 1,562 metabolic features were analyzed using linear trend models with multiple testing correction. Significant metabolites were further investigated through metabolite-level genome-wide association studies (GWAS). Findings were externally validated in 1,121 colon cancer-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and in colorectal cancer GWAS meta-analysis.Results: The polyamine N-(3-acetamidopropyl)pyrrolidine)-2-one (Acisoga) showed statistically significant increasing trends across colorectal cancer progression (P = 2.8 & times; 10-5). The association was independently validated in EPIC [odds ratio (OR) = 1.23; 95% confidence interval, 1.01-1.50). Metabolite-level GWAS identified genome-wide significant loci, including OPCML, EWSAT1, CTBP2, and CMKLR1. Genetically predicted Acisoga levels were positively associated with colorectal cancer risk (P = 0.003), with consistent results in sensitivity analyses using previously reported Acisoga-associated variants.Conclusions: We show a reproducible association between Acisoga and colorectal cancer progression and risk, supported by metabolomic, genetic, and external data. This integrative approach advances the understanding of metabolic processes involved in colorectal cancer and supports further evaluation of Acisoga in risk research.Impact: This work supports Acisoga as a potential circulating biomarker for colorectal cancer risk, with implications for early detection and prevention in screening populations.