A novel model for high-grade transformation in IDH mutant glioma (Methylation Analysis)

Background. High-grade transformation (HT) is common in IDH-mutant glioma, which is inevitable and unpredictable. Both genomic and metabolomic landscapes are going through dynamic processes during the transformation. Although HT phenomena have been observed clinically, the research of mechanisms underlying HT have been limited by the lack of preclinical models that can recapitulate the evolution of malignant transformation. Methods. Here we established a unique pair of matched cell lines, 403L and 403H, by utilizing tumor samples of an IDH-mutant astrocytoma from the same patient when the tumor was diagnosed as WHO grade 2 and 4, respectively. Using genetic, epigenetic, and metabolomic analyses, the two cell models have been characterized extensively. The cell lines have been used to establish orthotopic xenograft models of the disease. UMAP analysis was employed to investigate DNA methylation profiling of the tumors using methylation-based classifiers of the central nervous system (CNS) tumorsclustering using tSNE and UMAP analysis. Next, a comprehensive examination of DNA methylation patterns across the genomes of the two cell lines, 403L and 403H, was conducted. The analysis covered over 742,000 CpG sites in both cell lines.