Fig. 1

Progression to grade 4 is associated with increased hypoxia response, proliferation, and DNA repair. a The discovery cohort comprises six patients with IDHmut low-grade gliomas and relapsed grade 4 tumors. Cases TG01–TG05 were analyzed with WGS and TG01–TG06 with RNA-seq. A larger in-house IDHmut astrocytoma cohort was subjected to targeted DNA-sequencing for validation. In addition, 59 TCGA-ICGC WGS samples, 595 TCGA diffuse glioma RNA-seq samples, and 79 matched GLASS IDHmut astrocytoma samples were used as public validation data cohorts. SNV: single nucleotide variant. b Clinical courses of the patients in the discovery cohort. All six patients received radiation treatment and most patients received chemotherapy, but not TMZ, before progressing to grade 4. Vertical black lines represent surgeries and resected samples shown in gray were not measured as part of the discovery cohort. A: astrocytoma, OA: oligoastrocytoma. Tumor type is followed by the tumor grade. c Representative H&E images of the tumors in the discovery cohort with scale bars corresponding to 250 µm (low magnification) and 50 µm (high magnification). d More protein-altering mutations were detected in TG01 than in other cases (TG02–TG05) in the WGS data. e TG01 samples with full MSH2 deletion and DNMT3A inactivation showed a clear CG > TG substitution signature. f–g GO enrichment analysis for upregulated (f) and downregulated (g) genes. Upregulated genes were related to DNA repair, cell proliferation, and angiogenesis, whereas downregulated genes were associated with GPCR signaling pathways and the regulation of development. h Hypoxia response, cell cycle G2/M-phase, and S-phase gene set Z-score activities were upregulated in grade 4 tumors, except for TG01b, where proliferation activities slightly decreased. Gene set activities were scaled between 0 and 1 for visualization