Document Type : Research Articles
Authors
1
Zoology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo 11884, Egypt.
2
Molecular Pathology Laboratory, Children Cancer Hospital 57357, Cairo, Egypt.
3
Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, 11884, Egypt.
4
Center for Genetic Engineering- Al-Azhar University, Nasr City, Cairo, 11884, Egypt.
5
Molecular Genetics and Molecular Diagnostics, Molecular Diagnostics and Therapeutics Department, Genetic Engineering and Biotechnology Research Institute, University of Sadat City, Menofia, Egypt.
Abstract
Background: The molecular pathogenesis of hepatocellular carcinoma (HCC) exhibits striking etiological heterogeneity, with non-HCV-associated cases representing an increasingly prominent clinical challenge in regions like Egypt, where environmental carcinogens significantly contribute to the disease burden. Methods: Through integrated analysis of genomic data Egyptian cohort comprising 48 HCC cases (23 non-HCV, 25 HCV-positive) was examined and validated against TCGA/ICGC datasets using cBioPortal and Cytoscape. Results: This study identifies a distinct oncogenic program in non-viral HCC characterized by recurrent alterations in receptor tyrosine kinases (RTKs) FGFR1, MET, ERBB2 and FLT3. These mutations were found to be 4.3-fold more prevalent in non-HCV HCC compared to viral counterparts (26.1% vs. 6.0%, p=0.008), demonstrating strong etiological specificity. Functional characterization revealed these alterations converge on MAPK and PI3K-AKT-mTOR signaling cascades through shared adaptor proteins, creating an interconnected signaling network that drives tumor progression. Conclusion: Clinically, FGFR1/MET co-alterations predicted significantly worse outcomes (HR=2.3 for recurrence, 95% CI 1.1-4.8), while maintaining 92% specificity for non-viral HCC diagnosis. These findings establish the FGFR1-MET-ERBB2 axis as both a molecular classifier and therapeutic target, providing a rationale for etiology-specific management strategies in HCC precision oncology.
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