10254-CB-10 Comprehensive Analysis of Genetic Determinants of Tumor Formation and Malignant Transformation Using Glioma Patient-Derived Xenograft Models

Abstract Background Gliomas exhibit remarkable phenotypic diversity in tumor formation capacity, growth patterns, invasiveness, and therapeutic responses even within identical tumor subtypes. The molecular mechanisms underlying this phenotypic diversity remain poorly understood, posing barriers to personalized therapy. This study aimed to identify genetic determinants governing phenotypic diversity through large-scale patient-derived xenograft (PDX) model analysis and elucidate their biological significance. Methods We attempted to establish PDX models from 279 glioma cases and performed molecular diagnosis and copy number alteration (CNA) analysis for both patient samples and PDX models. Comprehensive genomic profiling using cancer genome panels was additionally conducted in 127 cases (46%). Associations between tumor formation capacity, growth patterns, invasiveness, and genetic alterations were examined using multivariate logistic regression analysis, followed by functional validation experiments for identified candidate genes. Results In glioblastoma, IDH-wildtype (GBM), TP53 loss (OR 1.52, 95%CI: 1.02-2.24, p = 0.031) and CDKN2A deletion (OR 3.24, 95%CI: 1.34-7.81, p = 0.009) were significantly associated with PDX formation capacity. EGFR amplification was a strong predictor of shortened patient survival (p = 0.002) and diffuse growth patterns (OR 7.00, 95%CI: 2.32-21.1, p = 0.001), with functional validation confirming shortened PDX survival (p < 0.001). Analysis of paired primary-recurrent specimens from molecular GBM (mGBM) revealed that acquisition of RTK amplifications (EGFR, PDGFRA) and Chr7+/10- led to malignant transformation to histological GBM and acquisition of PDX formation capacity. Conclusions This represents the largest-scale analysis of GBM-PDX models, identifying TP53 and CDKN2A deletions as molecular determinants of tumor formation, while EGFR amplification serves as a malignancy-defining factor. We also demonstrated the critical role of RTK amplifications and chromosomal abnormalities in mGBM progression to histological GBM, providing important insights into glioma biological diversity.