Landscape of cancer associated EpCAM mutations: molecular modeling, predictive insights and impact on patient survival
Abstract 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 metast...
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BMC
2025-07-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-025-14455-8 |
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| author | Priyanka S. Dhotare Audrey C. Bochi-Layec Timothy P. Fleming William E. Gillanders Ross M. Bremner Kailas D. Sonawane Narendra V. Sankpal |
| author_facet | Priyanka S. Dhotare Audrey C. Bochi-Layec Timothy P. Fleming William E. Gillanders Ross M. Bremner Kailas D. Sonawane Narendra V. Sankpal |
| author_sort | Priyanka S. Dhotare |
| collection | DOAJ |
| description | Abstract 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. From an analysis of 300 studies comprising 300,300 cancer samples, we identified 160 recurrent somatic mutations across epithelial cancers. Of these, seven mutations most frequently associated with lung cancer were further validated through molecular dynamics simulations, evaluation of ERK signaling activity, and assessment of sensitivity to the MEK inhibitor Trametinib. 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. |
| format | Article |
| id | doaj-art-29cc84690c88497ca1b8286cece3a79d |
| institution | Kabale University |
| issn | 1471-2407 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj-art-29cc84690c88497ca1b8286cece3a79d2025-08-20T03:38:18ZengBMCBMC Cancer1471-24072025-07-0125111910.1186/s12885-025-14455-8Landscape of cancer associated EpCAM mutations: molecular modeling, predictive insights and impact on patient survivalPriyanka S. Dhotare0Audrey C. Bochi-Layec1Timothy P. Fleming2William E. Gillanders3Ross M. Bremner4Kailas D. Sonawane5Narendra V. Sankpal6Shivaji UniversitySchool of Medicine, Washington UniversityNorton Thoracic Institute, St. Joseph’s Hospital and Medical CenterSchool of Medicine, Washington UniversityNorton Thoracic Institute, St. Joseph’s Hospital and Medical CenterShivaji UniversityNorton Thoracic Institute, St. Joseph’s Hospital and Medical CenterAbstract 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. From an analysis of 300 studies comprising 300,300 cancer samples, we identified 160 recurrent somatic mutations across epithelial cancers. Of these, seven mutations most frequently associated with lung cancer were further validated through molecular dynamics simulations, evaluation of ERK signaling activity, and assessment of sensitivity to the MEK inhibitor Trametinib. 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.https://doi.org/10.1186/s12885-025-14455-8EpCAMMutationCancerMolecular modelling |
| spellingShingle | Priyanka S. Dhotare Audrey C. Bochi-Layec Timothy P. Fleming William E. Gillanders Ross M. Bremner Kailas D. Sonawane Narendra V. Sankpal Landscape of cancer associated EpCAM mutations: molecular modeling, predictive insights and impact on patient survival BMC Cancer EpCAM Mutation Cancer Molecular modelling |
| title | Landscape of cancer associated EpCAM mutations: molecular modeling, predictive insights and impact on patient survival |
| title_full | Landscape of cancer associated EpCAM mutations: molecular modeling, predictive insights and impact on patient survival |
| title_fullStr | Landscape of cancer associated EpCAM mutations: molecular modeling, predictive insights and impact on patient survival |
| title_full_unstemmed | Landscape of cancer associated EpCAM mutations: molecular modeling, predictive insights and impact on patient survival |
| title_short | Landscape of cancer associated EpCAM mutations: molecular modeling, predictive insights and impact on patient survival |
| title_sort | landscape of cancer associated epcam mutations molecular modeling predictive insights and impact on patient survival |
| topic | EpCAM Mutation Cancer Molecular modelling |
| url | https://doi.org/10.1186/s12885-025-14455-8 |
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