Landscape of cancer associated EpCAM mutations: molecular modeling, Predictive Insights and Impact on Patient Survival

Background EpCAM (epithelial cell adhesion molecule) is a key regulator of epithelial cell-cell adhesion, signal transduction, tissue regeneration, and serves as a stem cell marker. It is frequently overexpressed in epithelial cancers and is linked to tumor progression, survival, and metastasis. However, the functional impact of EpCAM mutations in cancer remains poorly understood. Methods To investigate the role of EpCAM mutations, we performed a comprehensive analysis of cancer cohorts from multiple genomic datasets, identifying novel somatic EpCAM mutations across diverse epithelial cancers. Using bioinformatics tools (SIFT, PolyPhen-2, Mutation Assessor) and molecular modeling, we assessed the potential impact of these mutations. Further, homology modeling and all-atom molecular dynamics (MD) simulations were conducted to evaluate structural changes. Results Our findings revealed that cancer-associated mutations, particularly in the TY-1 and RCD regions, induce structural instability in EpCAM, leading to altered functional properties. Patient cohort analyses indicated that EpCAM mutations correlate with reduced survival rates in colon and hepatocellular carcinoma and contribute to early tumor progression in lung cancer. Moreover, introducing these mutations into lung cancer cells enhanced their sensitivity to MEK inhibitors, suggesting a potential therapeutic vulnerability. Conclusion This study provides novel insights into the structural and functional consequences of EpCAM mutations in cancer, demonstrating their association with reduced survival, tumor progression, and drug sensitivity. These findings highlight EpCAM as a promising therapeutic target in epithelial cancers.