Abstract 285: Integration of serum and tumor metabolomics reveals distinct metabolic profiles in early onset colorectal cancer

Abstract Introduction: Early onset colorectal cancer (EOCRC) is rising at an alarming rate and is increasingly recognized as a distinct clinical entity from average onset (AO) CRC. However, the molecular underpinnings remain largely unknown. We found key differences at the transcriptomic level that highlighted the enrichment of several metabolic pathways that are distinct in the EOCRC (<50 years old) compared to the AOCRC population, prompting further study of the association between age of onset and role of metabolomics. To this end, we sought to highlight differences in the metabolic profile of EOCRC patients compared to AOCRC. Methods: Banked serum samples from the Roswell Park Data Bank and biorepository were obtained from EOCRC (n=25) and AOCRC (n=25) patients, as well as age-matched non-disease (n=10) populations. Further, matched tumor samples from AOCRC (n=25) and EOCRC (n=25) were obtained. Comprehensive metabolomics via mass spectrometry was conducted on both the serum and matched tumors. Metabolite abundances from serum and tumors were assessed independently. Abundances were log2 transformed to achieve a normal distribution. Prior to differential metabolite abundance, patient data were assessed for outliers and necessary co-variates (e.g., sex, race, etc.). Differential abundance was assessed via the generation of linear mixed models and analyses of variances with p≤0.05 set for statistical significance. Results: Samples were well-matched at baseline for relevant demographics aside from age. When integrating serum and tumor metabolites, after adjusting for biological sex, there were eight significantly altered metabolites. These were primarily lipids, including phosphatidylcholines, lysophosphatidylcholines, sphingolipids, and ceramides. All of these were increased in AOCRC compared to EOCRC. Conversely, hypoxanthine and hexosylceramides were found to be increased in the EOCRC compared to AOCRC. Further, we observed significant differences in metabolite expression by biological sex, with AO female tumor samples also enriched for lipids like phosphatidylcholine, sphingolipids, and ceramides, as compared to AO males. Conclusion: Metabolomics assessment of CRC patients demonstrated significant differences in metabolite concentrations between EOCRC and AOCRC patients in both serum and tumor samples. Further, these differences were strongly correlated with patients’ sex, suggesting a biological influence of sex on CRC pathogenesis. Altogether, these results imply a distinct metabolic phenotype among the EOCRC population. Given the reported role of hypoxanthine and hexosylceramides in CRC metastasis, further studies should investigate their influence on clinical outcomes and treatment response. Citation Format: Deepak Vadehra, Spencer Rosario, Timothy J. Brown, Hua- Hsin Hsaio, Sarbajit Mukherjee. Integration of serum and tumor metabolomics reveals distinct metabolic profiles in early onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 285.