Association of EGFR gene amplification with spatial gene susceptibility and gene functional modularity in glioblastoma

Background: Glioblastoma (GBM) exhibits marked spatial heterogeneity. This study aimed to investigate the spatial distribution patterns and gene co-expression modules associated with epidermal growth factor receptor (EGFR) amplification. Methods: A total of 131 GBM cases from The Cancer Genome Atlas were classified into high-level EGFR-amplified and low/non-amplified groups. Tumor masks were generated from magnetic resonance imaging scans in The Cancer Imaging Archive to map contrast-enhancing, necrotic and peritumoral edema regions. Voxel-wise frequency and regional susceptibility were calculated to construct differential frequency maps. Weighted gene co-expression network analysis identified EGFR-related gene modules, which were then projected onto the Allen Human Brain Atlas to explore transcriptional correlations with spatial tumor patterns. Results: High-level EGFR-amplified tumors were enriched in the medial temporal lobe and cingulate gyrus, while low/non-amplified tumors were more frequent in the frontal, parietal, and insular cortices. Four gene modules (MEcyan, MEblack, MEblue, MEpink) showed significant correlations with EGFR amplification. MEpink and MEblack were strongly associated with EGFR amplification in the occipital lobe (R = 0.77, 0.78), whereas MEred showed a negative correlation in the temporal lobe (R = −0.63). Functional enrichment revealed involvement in synaptic transmission, myelination, and immunometabolic processes. Conclusion: EGFR amplification in GBM demonstrates region-specific enrichment and is associated with distinct gene co-expression modules related to neural and immune pathways. These findings may inform the development of spatially targeted molecular therapies.