Multiomics Dissection of Early-Onset Colorectal Cancer (EOCRC) Reveals an Immunosuppressive Microenvironment and Identifies FAT3 Mutation as a Biomarker of Hot-Like Immune Features.

Early-onset colorectal cancer (EOCRC) exhibits distinct clinical and biological features compared with late-onset CRC (LOCRC), yet its genomic architecture and immune microenvironmental determinants remain incompletely characterized. Here, we integrated multiomics discovery analyses of 69 EOCRC and 461 LOCRC patients from the TCGA cohort, complemented by independent validation, single-cell RNA sequencing, spatial transcriptomics, and systems-level network analysis. We identified 10 genes significantly enriched for mutations in EOCRC, including ANXA7, ZNF267, and POLQ, which displayed distinct domain-specific clustering and were validated in an external cohort. Mutational signature decomposition showed that EOCRC was associated with an SBS87-like signature, whereas LOCRC was dominated by SBS1; because TCGA lacks detailed treatment history, this SBS87-like inference should not be interpreted as direct evidence of prior thiopurine exposure. Immunologically, EOCRC displayed an immunosuppressive microenvironment characterized by elevated regulatory T cells, resting NK cells, and tighter immune-stromal coupling, as further supported by spatial transcriptomic analysis. Single-cell atlas analysis identified M2-polarized, SPP1-expressing macrophage subsets in EOCRC. Weighted gene coexpression network analysis identified a mitochondrial-ribosomal biogenesis module as the transcriptional hallmark of EOCRC. Finally, random forest analysis identified FAT3 mutations as a genomic correlate of a hot-like, immune-activated phenotype in EOCRC. Integrative single-cell analysis localized FAT3 predominantly to cancer-associated fibroblasts, especially myofibroblasts, and an in silico FAT3 perturbation analysis suggested potential downstream programs involving extracellular matrix remodeling, inflammatory signaling, chemokine response, and mitotic spindle regulation. These findings delineate age-stratified genomic and microenvironmental features of EOCRC and generate testable hypotheses for future functional and clinical validation.