IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas
Open accessAbstract
IDH1 encodes isocitrate dehydrogenase 1, which participates in the citric acid cycle and was recently reported to be mutated in 12% of glioblastomas. We assessed IDH1 mutations in 321 gliomas of various histological types and biological behaviors. A total of 130 IDH1 mutations was detected, and all were located at amino acid residue 132. Of these, 91% were G-->A mutations (Arg-->His). IDH1 mutations were frequent in low-grade diffuse astrocytomas (88%) and in secondary glioblastomas that developed through progression from low-grade diffuse or anaplastic astrocytoma (82%). Similarly, high frequencies of IDH1 mutations were found in oligodendrogliomas (79%) and oligoastrocytomas (94%). Analyses of multiple biopsies from the same patient (51 cases) showed that there were no cases in which an IDH1 mutation occurred after the acquisition of either a TP53 mutation or loss of 1p/19q, suggesting that IDH1 mutations are very early events in gliomagenesis and may affect a common glial precursor cell population. IDH1 mutations were co-present with TP53 mutations in 63% of low-grade diffuse astrocytomas and with loss of heterozygosity 1p/19q in 64% of oligodendrogliomas; they were rare in pilocytic astrocytomas (10%) and primary glioblastomas (5%) and absent in ependymomas. The frequent presence of IDH1 mutations in secondary glioblastomas and their near-complete absence in primary glioblastomas reinforce the concept that despite their histological similarities, these subtypes are genetically and clinically distinct entities.
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IDH1 mutations are early events in glial cancer development, raising the possibility that additional oncogenic mutations render GBM tumors less dependent on mutant IDH for proliferation and progression.
“IDH1 mutations are early events in the development of glial cancer (Watanabe et al., 2009), raising the possibility that IDH mutations are important for tumor initiation, but accumulation of additional oncogenic mutations renders GBM tumors less dependent on constitutive expression of mutant IDH for tumor proliferation and progression (Johnson et al., 2014; Wakimoto et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Watanabe et al., 2009
IDH mutations occur early in disease progression.
“the finding that IDH mutations occurred early in disease progression (Watanabe et al., 2009)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Watanabe et al., 2009
D-2-HG impairs necroptosis and the small GTPase Cdc42, leading to suppression of MLK3-mediated apoptosis.
“Finally, D-2HG also impairs necroptosis and the small GTPase Cdc42, leading to suppression of mixed lineage kinase 3 (MLK3)-mediated apoptosis140,141.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [140]
Suppression of RIP3-mediated necroptosis and MLK3-mediated apoptosis by D-2-HG may contribute to IDH-mutant carcinogenesis.
“These findings therefore suggest that both suppression of RIP3-mediated necroptosis and MLK3-mediated apoptosis by D-2-HG may contribute to IDH-mutant carcinogenesis140,141.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [140]
D-2-HG binds DNA methyltransferase DNMT1, which represses RIP3.
“D-2-HG has also been found to bind the DNA methyltransferase DNMT1, which subsequently represses receptor-interacting protein kinase 3 (RIP3).”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [140]
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- Authors
- Watanabe, T., Nobusawa, S., Kleihues, P., & Ohgaki, H.
- Affiliations
- Centre international de recherche sur le cancer (FR)
- University Hospital Zurich (CH)
- Corresponding author
- Ohgaki, Hiroko
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 174
- Issue
- 4
- Pages
- 1149-1153
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2671348
- OpenAlex
- W2112495947
- Cited by
- 1,027
- References
- 19
- Citations by year
- 2026: 14 · 2025: 29 · 2024: 38 · 2023: 46 · 2022: 50 · 2021: 54 · 2020: 55 · 2019: 56 · 2018: 69 · 2017: 68 · 2016: 62 · 2015: 76 · 2014: 77 · 2013: 76 · 2012: 80
- FWCI
- 40.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Foundation for Promotion of Cancer Research
- Naito Foundation
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- IDH1 mutation, isocitrate dehydrogenase, glioma, diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, secondary glioblastoma, primary glioblastoma, TP53 mutation, 1p/19q codeletion, gliomagenesis, tumor progression, pilocytic astrocytoma, ependymoma, glial precursor cells
- MeSH terms
- Adult, Age Factors, Astrocytoma, Brain Neoplasms, Female, Humans, Isocitrate Dehydrogenase, Male, Middle Aged, Mutation, Oligodendroglioma, Biomarkers, Tumor, Tumor Suppressor Protein p53, Polymorphism, Single-Stranded Conformational
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