Abstract C122: Early-onset colorectal cancer is associated with a coordinated epithelial-mesenchymal transition and tumor-plasticity transcriptional program across a diverse cohort

Abstract

Early-onset colorectal cancer (EOCRC, diagnosed before age 50) is rising in incidence worldwide, but whether EOCRC tumors exhibit transcriptional programs distinct from later-onset colorectal cancer (LOCRC) remains incompletely defined, particularly across populations with a high burden of EOCRC. We performed transcriptome-wide profiling of 679 formalin-fixed paraffin-embedded (FFPE) stage I–III colorectal tumors from four racial/ethnic populations (Alaska Native, African American, Hispanic, and non-Hispanic White; 78 EOCRC, 601 LOCRC) in the Translational Research Program in Cancer Differences across Populations (TRPCDP) and externally validated findings in The Cancer Genome Atlas (TCGA). Differential expression used a winsorized DESeq2 framework adjusting for sex, population, microsatellite instability (MSI) status, tumor site, stage, year of diagnosis, and sequencing plate; coordinated pathway differences were identified by Hallmark gene set enrichment analysis (GSEA) with Benjamini-Hochberg false discovery rate (FDR) across all 50 Hallmark gene sets. Compared with LOCRC, EOCRC was not characterized by widespread large-effect single-gene differences; the dominant signal emerged at the pathway level. ZNF304, a zinc-finger transcriptional regulator, was the single FDR-significant differentially expressed gene (p = 2.3 × 10-6; FDR = 0.042) and was expressed more highly in younger patients. At the pathway level, EOCRC tumors showed enrichment of epithelial-mesenchymal transition (EMT), apical junction, hypoxia, angiogenesis, TGFβ, TNFα/NFκB, complement, and inflammatory signaling, alongside lower oxidative phosphorylation, interferon-α response, MYC targets, and E2F/G2M cell-cycle programs (29 of 50 Hallmark sets at FDR < 0.05). Findings were directionally consistent across limma-voom and inverse-probability-weighted (IPW) sensitivity models and were robust to the low-expression gene filter. In TCGA-COAD/READ (n = 603; 76 EOCRC), ZNF304 showed the same direction of effect (nominal p = 1.5 × 10-3; not FDR-significant), and the EMT (NES = +2.22), oxidative phosphorylation (NES = −2.21), interferon-α (NES = −2.10), and apical junction (NES = +1.56) programs replicated at FDR < 0.05. Within the same TRPCDP cohort, the EOCRC pathway program was positively correlated with the transcriptional program associated with CRC-specific mortality (Hallmark NES correlation r = 0.74 across all 50 sets), with EMT most strongly enriched in both. These findings indicate that EOCRC tumors are characterized by a coordinated tumor-plasticity program, EMT and stromal remodeling with lower oxidative phosphorylation and interferon-α response, that cross-cohort validates in TCGA and overlaps a program associated with CRC-specific mortality, suggesting EOCRC tumors may be biologically primed toward invasion and metastatic potential beyond differences explained by stage, site, or standard molecular subtype alone. Scott D. LaBrie. Early-onset colorectal cancer is associated with a coordinated epithelial-mesenchymal transition and tumor-plasticity transcriptional program across a diverse cohort [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr C122.