The classification of IDH-mutant gliomas according to the World Health Organization Classification of Tumors of the Central Nervous System 2021 is summarized in the table below:
| Tumor Type | IDH Status | 1p/19q Status | Key Features | Available Grades |
|---|---|---|---|---|
| Astrocytoma IDH-mutant | Mutant | Intact | ATRX loss, TP53 mutation | Grade 2, 3, or 4 |
| Oligodendroglioma IDH-mutant and 1p/19q-codeleted | Mutant | Codeleted | TERT promoter mutation, ATRX retained | Grade 2 or 3 |
| Glioblastoma | Wildtype | — | TERT/EGFR amplification or +7/−10 signature, or necrosis/microvascular proliferation | Always Grade 4 |
glioblastoma, IDH-mutant is no longer used. These tumors are now classified as Astrocytoma, IDH-mutant, Grade 4.Although IDH-mutant glioma generally has a better prognosis than its IDH-wildtype counterparts, considerable prognostic heterogeneity persists among patients with the same IDH mutation. A study of Wang et al. has primarily focused on the different IDH statuses or grades, while the metabolic heterogeneity within IDH-mutant gliomas remains insufficiently characterized. This study aims to identify transcriptomic metabolic subtypes and associated immune microenvironment differences to better understand survival variability and potential therapeutic targets in IDH-mutant glioma.
Patients with IDH-mutant gliomas were included from four public datasets (TCGA, n = 373; CGGA325, n = 167; CGGA693, n = 333; GLASS, n = 100), supplemented by 22 cases from Beijing Tiantan Hospital as an independent cohort. Consensus clustering was used to define novel metabolic subtypes. Clinical features were assessed using chi-square tests and Kaplan-Meier analysis. Metabolic profiles were characterized through enrichment analysis and GSVA; immune infiltration was analyzed using CIBERSORTx and ESTIMATE. Tumor samples from the independent cohort underwent untargeted metabolomics for validation. LASSO regression was applied to select metabolic signatures, and the CGP2014 drug library was used for drug screening.
Three metabolic subtypes (C1-C3) with distinct prognoses (p < 0.05) were identified. C1 exhibited enhanced carbohydrate and nucleotide metabolism; C2 displayed upregulated amino acid and lipid metabolism; and C3 demonstrated elevated lipid, nucleotide, and vitamin metabolism. These patterns were validated in the independent cohort. Subtypes were also correlated with immune infiltration. A 13-gene metabolic signature was established to stratify prognostic risk and suggest subtype-specific drug sensitivities.
The study provided a novel metabolic subtype for IDH-mutant glioma and highlighted these patients' metabolic heterogeneity and potential therapeutic strategies 1)
Wang et al. provide compelling evidence that metabolic subtyping in IDH-mutant gliomas is biologically meaningful and prognostically informative. Despite the limitations of validation scope and functional depth, the study opens promising avenues for metabolism-guided precision neuro-oncology.
IDH-mutant gliomas, although generally associated with better prognosis, show considerable biological and clinical heterogeneity. Recent transcriptomic and metabolic profiling has revealed distinct subtypes with prognostic and therapeutic implications.
| Subtype | IDH Status | 1p/19q Status | Common Features | WHO Grades |
|---|---|---|---|---|
| Astrocytoma, IDH-mutant | Mutant | Intact | TP53 mutation, ATRX loss | Grade 2, 3, or 4 |
| Oligodendroglioma, IDH-mutant | Mutant | Codeleted | TERT promoter mutation, ATRX retained | Grade 2 or 3 |
| Subtype | Dominant Metabolism | Prognosis | Immune Microenvironment | Notes |
|---|---|---|---|---|
| C1 | Carbohydrate & nucleotide metabolism | Poor | Less immune infiltration | Higher proliferation signature |
| C2 | Amino acid & lipid metabolism | Intermediate | Moderate immune activity | May benefit from lipid metabolism-targeted drugs |
| C3 | Lipid, nucleotide & vitamin metabolism | Favorable | Higher immune infiltration | Most differentiated; possible immunogenic role |