INTERNATIONAL CONGRESS OF
CancerGenetics
EGFR L861Q in Glioblastoma: From Computational Prediction of Structural destabilization to Clinical Correlation and Survival Impact
-
Fatemeh Arefnejad ,1,*
- Introduction: Glioblastoma multiforme (GBM) represents the most aggressive primary brain tumor in adults, constituting 45.2% of malignant central nervous system neoplasms. Despite multimodal therapies, GBM portends a dismal prognosis with a median survival of 15 months and a five-year survival rate of 5.5%. The epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, regulates cellular proliferation, survival, migration, and differentiation. Its oncogenic role in various cancers has driven substantial research and therapeutic development. The L861Q missense mutation (rs121913444), situated within the tyrosine kinase domain, is established in NSCLC as a biomarker for tyrosine kinase inhibitor sensitivity. However, its prevalence, pathogenicity, and clinical significance within GBM remain inadequately explored. This investigation employs comprehensive bioinformatic methodologies to characterize the structural, functional, and clinical implications of EGFR L861Q in GBM.
- Methods: The initial phase involved systematic identification of recurrent somatic missense mutations using cBioPortal and TCGA-GBM data. Variant selection criteria included: notable allele frequency in GBM, low population frequency (MAF < 0.01), and lack of prior investigation in GBM despite known roles in other cancers. Comprehensive characterization utilized ClinVar, UniProt (P00533), and dbNSFP. Pathogenicity predictions employed SIFT, PolyPhen-2, PANTHER, and MetaRNN. Structural analysis integrated multiple approaches: HOPE with WHAT IF modeled atomic-level effects, NetSurfP predicted solvent accessibility and secondary structure, and ProtScale with Kyte & Doolittle quantified hydrophobicity changes. Protein network reconstruction used STRING (v11.5; confidence >0.7) with functional enrichment. Pathway contextualization used the KEGG glioma pathway (map05214). Expression profiling via GEPIA2 included differential expression analysis, pan-cancer comparison, survival analysis, and isoform-specific correlations. Evolutionary conservation was assessed with ConSurf via cross-species alignments. Statistical significance was p < 0.05 using Student's t-test and log-rank test.
- Results: Pathogenicity assessment via PANTHER and MetaRNN (score: 0.913) confirmed the deleterious nature of EGFR L861Q, supported by evolutionary conservation showing exceptional leucine 861 conservation across species, indicating its critical role in the tyrosine kinase domain. The leucine to glutamine substitution is predicted to disrupt catalytic function. Structural characterization revealed substantial biophysical alterations through ProtScale analysis (Kyte & Doolittle algorithm), showing a dramatic hydrophobicity shift (-7.3 units) from hydrophobic leucine (index: +3.8) to hydrophilic glutamine (index: -3.5). NetSurfP analysis identified significantly increased solvent accessibility (RSA: 29% to 42%; ASA: 59 Ų to 95 Ų) and substantial backbone conformational changes (Φ: -98° to -92°; Ψ: 101° to 125°), with the mutation destabilizing upstream secondary structures despite maintaining local β-sheet configuration. Clinical analysis via cBioPortal identified this mutation in GBM with notable allele frequency (0.46), showing distinct disease-specific patterns: frequent co-occurrence with other EGFR alterations in GBM versus concomitant TP53/RB pathway mutations in lung cancers. This mutation represents a distinct class located outside conventional GBM mutation hotspots (FURIN-like and GF-recep-IV domains), yet demonstrates strong association with glioblastogenesis. Protein interaction analysis using STRING revealed extensive networks with HER family partners (ERBB2, ERBB3), ligands (EGF, HBEGF), downstream effectors (GAB1, PIK3CA, ERRFI1), regulators (CBL), and extracellular components (DCN, CDH1). KEGG pathway analysis (map05214) confirmed association with primary glioblastoma pathogenesis, showing activation of oncogenic cascades (RAS-RAF-MEK-ERK and PI3K-AKT-mTOR) and intersection with p53, RB, and PDGF signaling networks. Expression analysis via GEPIA2 demonstrated dramatic EGFR upregulation in GBM (82.35 TPM vs 3.99 TPM in normal tissue, p < 0.01), with survival analysis showing significant divergence after 35 months where high-expression cohorts experienced sharply declining survival. Isoform-specific analysis confirmed pathogenic potential in tyrosine kinase domain-containing isoforms (EGFR-001, EGFR-002, EGFR-202). These integrated results establish EGFR L861Q as a clinically significant variant in glioblastoma through multiple molecular mechanisms, demonstrating strong pathogenic evidence, substantial structural impact, distinct molecular patterns, network integration with key signaling pathways, significant overexpression, and survival correlation.
- Conclusion: This comprehensive investigation provides compelling evidence for the pathogenic significance of EGFR L861Q in glioblastoma pathogenesis. The mutation induces substantial biophysical alterations, shows distinctive co-mutation patterns in GBM versus lung cancer, and associates with aggressive clinical phenotypes. The significant overexpression and correlation with poor survival underscore its clinical relevance. These findings advocate for recognizing L861Q as a context-specific oncogenic driver in GBM and warrant further investigation into its potential as both a prognostic biomarker and therapeutic target. Functional validation studies and clinical correlation analyses are essential to translate these computational insights into clinical applications.
- Keywords: EGFR L861Q, Glioblastoma, Bioinformatic Analysis, Prognostic Biomarker, Therapeutic Target
