Distinct genomic and pathway-level alterations in early-onset colorectal cancer: A large-scale Korean cohort analysis

Background: Early-onset colorectal cancer (EOC) is rising in incidence globally, yet its genomic landscape in Asian populations remains inadequately characterized. Understanding molecular differences between EOC and traditional-onset colorectal cancer (TOC) is essential for clarifying age-related tumor biology. Patients and methods: Genomic profiles from 1,675 nationwide colorectal cancer patients (2017-2021) were analyzed using targeted next-generation sequencing. EOC was defined as diagnosis at ≤50 years and TOC as >50 years. Mutational frequencies, spectra, pathway enrichment, and co-occurrence patterns were compared between EOC and TOC using R-based pipelines, including Fisher's exact test with FDR adjustment and maftools. Functional and protein-protein interaction analyses (DAVID, Metascape/MCODE) were performed to identify enriched pathways, and HRD-associated genes were additionally assessed for nonsense and frameshift loss-of-function variants. Results: Among 1,675 patients (428 EOC; 1,247 TOC), EOC showed higher rates of TMB-high tumors (18% vs. 12%, p = 0.009) and MSI-high tumors (5.1% vs. 2.2%, p = 0.003), indicating a greater prevalence of hypermutated phenotypes in younger individuals. EOC also demonstrated higher mutation rates in SMAD4, FAT3, and KMT2D , each increased by approximately 3-4% compared with TOC. In contrast, classical colorectal cancer drivers such as APC, KRAS, TP53 , and WNT -related genes were more frequently altered in TOC. In mutational spectrum analysis, EOC exhibited a modestly higher transition-to-transversion ratio, consistent with greater intrinsic genomic instability. Pathway analysis demonstrated enrichment of NOTCH, PI3K, Hippo, TGF-beta, cell-cycle, and MYC pathways in EOC, while RTK-RAS and WNT pathways predominated in TOC. Ninety-one genes showed significantly higher mutation frequencies in EOC (FDR < 0.05). Loss-of-function mutations in HRD-related genes ( BRCA1/2, PALB2, RAD51C/D, ATM, CHEK2 ) were also more frequent in EOC (11.4% vs. 8%), supporting the greater contribution of homologous recombination defects in early-onset disease. Co-occurrence network analyses revealed EOC-specific clusters involving chromatin remodeling and DNA repair modules, including a dominant DNA repair supercluster (log 10 (P) = -16.5 to -18.6), alongside enriched epigenetic and transcriptional regulation modules. Conclusions: EOC exhibits distinct genomic and pathway-level characteristics, including higher genomic instability and enrichment of chromatin remodeling and DNA repair. These findings indicate that EOC represents a biologically unique subtype of colorectal cancer that may benefit from age-specific or HRD-targeted therapeutic strategies. Future work integrating germline sequencing with somatic profiles will help more comprehensively clarify the age-related molecular features of EOC.