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Updated: Oct 3, 2025
A Protocol for Explant Cultures of IDH1-mutant Diffuse Low-grade Gliomas
Published on: May 9, 2025
[Precision Medicine for IDH-mutant Diffuse Glioma(Lower-grade Glioma)]
1Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University.
Abstract:
Several important revisions were made regarding the classification of brain tumors in the newest version(5th edition)of the WHO classification of tumours of the central nervous system published in 2021. Now, most so-called "lower-grade glioma(s)" fall into the category of IDH-mutant diffuse glioma, represented by astrocytoma and oligodendroglioma. For the diagnosis of these IDH-mutant gliomas, the determination of genetic alterations in IDH1/2, TP53, chromosome 1p/19q, ATRX, TERT promoter, and CDNK2A/B is important. Generally, in addition to the IDH mutation, astrocytomas have TP53 mutation and ATRX mutation, whereas oligodendrogliomas have 1p/19q codeletion and TERT promoter mutation. For tumor grading in the new WHO classification, astrocytomas harboring CDNK2A/B homozygous deletion can be categorized as WHO grade 4 astrocytomas, even though they do not have microvascular proliferation or necrosis. For these IDH-mutant tumors, molecular targeted therapy for IDH mutation has been under development. Several enzymatic inhibitors of IDH1/2 have been tested in clinical trials and were suggested to have some clinical effectiveness. Currently, large-scale trials are ongoing. Besides these inhibitors, other strategies for targeting IDH mutations, such as immunotherapy and therapy targeting aberrant metabolic pathways resulting from IDH mutation are also examined. These novel therapies will be beneficial to patients.
Insights
The 2021 WHO classification redefines gliomas, emphasizing IDH mutations. New grading criteria and targeted therapies, including IDH inhibitors, offer improved treatment for brain tumor patients.
Area of Science:
- Neuro-oncology
- Molecular Pathology
- Genetics
Background:
- The 5th edition of the WHO classification of CNS tumors (2021) introduced significant changes to glioma classification.
- Previously categorized
- lower-grade gliomas
- are now primarily classified as IDH-mutant diffuse gliomas, including astrocytoma and oligodendroglioma.
Purpose of the Study:
- To outline the key diagnostic genetic alterations for IDH-mutant gliomas.
- To explain the revised tumor grading criteria, particularly for astrocytomas.
- To review the development of targeted therapies for IDH-mutant gliomas.
Main Methods:
- Diagnosis relies on identifying specific genetic alterations: IDH1/2 mutations, TP53, 1p/19q codeletion, ATRX, TERT promoter, and CDKN2A/B.
- Astrocytomas typically show IDH, TP53, and ATRX alterations.
- Oligodendrogliomas are characterized by 1p/19q codeletion and TERT promoter mutations.
Main Results:
- The new WHO classification integrates molecular data for precise glioma diagnosis and grading.
- IDH-mutant astrocytomas with CDKN2A/B homozygous deletion are now WHO grade 4, irrespective of microvascular proliferation or necrosis.
- Clinical trials for IDH1/2 inhibitors show promise, with ongoing large-scale studies.
Conclusions:
- The revised classification enhances diagnostic accuracy and prognostic stratification of gliomas.
- Targeted therapies, including IDH inhibitors, immunotherapy, and metabolic pathway targeting, are emerging as promising treatment strategies for IDH-mutant gliomas.
- These novel therapeutic approaches hold potential for significant patient benefit.
