BACKGROUND: Patients with long-standing ulcerative colitis (UC) are at increased risk of developing colitis-associated colorectal cancer (UC-CRC). However, the molecular transition from chronic inflammation to neoplasia remains incompletely defined, and biomarkers for high-risk disease are still lacking. METHODS: Transcriptomic datasets from UC and CRC cohorts were analyzed independently to identify reproducible transcriptional alterations. Differential expression and pathway enrichment analyses were followed by stepwise prioritization of candidate genes based on expression in UC-associated neoplasia, prognostic relevance in CRC, and classification performance. Receiver operating characteristic analysis and composite z-score modeling were used to evaluate signature performance, whereas gene co-expression analysis and single-sample gene set enrichment analysis were used to examine its biological context. RESULTS: Epithelial-mesenchymal transition (EMT) emerged as a consistently enriched pathway among upregulated genes in UC and CRC. Intersection of EMT-associated genes identified 24 shared candidates, of which 14 were significantly upregulated in UC-associated neoplasia compared with quiescent UC and showed consistent upregulation across independent active UC datasets. These genes showed strong discriminatory performance (AUC > 0.85), and Random Forest analysis further refined a seven-gene panel (FAP, TIMP1, COL12A1, CALU, INHBA, SPP1, and CTHRC1). A composite z-score derived from this panel distinguished neoplastic from quiescent UC and showed a stepwise increase across disease states. Functional analyses linked the signature to EMT, hypoxia, angiogenesis, coagulation, and inflammatory signaling. CONCLUSIONS: This study identified a seven-gene EMT-associated signature linked to UC-associated neoplastic transformation. The signature may support molecular risk stratification in UC and provides a framework for future validation in surveillance settings.
Nevin Belder (Fri,) studied this question.