Distinct metabolic and genetic alterations in tumors from early-onset versus late-onset colorectal cancer

Abstract

Early-onset colorectal cancer (EO-CRC) occurring in individuals under age 50 is rapidly increasing globally, while the incidence of late-onset colorectal cancer (LO-CRC) has decreased over recent years. Previous studies have identified metabolites linked to CRC biology, however tumor-specific differences between EO-CRC and LO-CRC have not been explored. This study aimed to compare the tumor metabolome of EO-CRC and LO-CRC patients to reveal the unique biochemical state of EO-CRC. Mass spectrometry-based untargeted metabolomics was performed on tumor and patient-matched normal tissues from EO-CRC (n = 53) and LO-CRC (n = 314) patients to identify metabolites significantly altered in tumors (q ≤ 0.05). Metabolite set enrichment analysis, metabolic pathway, and network analyses were performed, to identify the relationship between the altered metabolites and biological function. Analysis revealed 155 metabolites significantly altered between normal and tumor tissues. Homovanillic acid , a metabolite of dopamine, was uniquely downregulated in EO-CRC. Despite shared changes to homovanillic acid-metabolizing genes between EO- and LO-CRC the disruption in catecholamine metabolism may be specific to EO-CRC biology. Pathway and network analysis, supported by gene expression validation, showed that PD-L1 was uniquely decreased in EO-CRC suggesting immunosuppression. Additionally, phospholipid signaling was favored in EO-CRC, whereas LO-CRC tumors showed alterations to EGFR signaling and oxidative stress-related genes. In summary, this study reveals the metabolic nuances in tumor tissues from patients with EO-CRC and LO-CRC, indicating catecholamine metabolism, phospholipid signaling and immunosuppression in the biology of EO-CRC. These findings provide new insight into the metabolism of EO-CRCs that may inform new therapeutic strategies for this group of CRC patients.