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Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH -Mutant Gliomas
Open accessPublished version of a preprint
Abstract
Purpose: Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. Methods: We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. Results: By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non–xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months; P = 0.0011). Conclusion: A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. Clin Cancer Res; 20(11); 2898–909. ©2014 AACR.
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“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 Wakimoto et al., 2014
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“Network analysis of the several driver mutation genes, including KMT2D138, PIK3CA139, PTEN140, and IDH1141, that regulate signaling and metabolic pathways in KRAS-driven cancers, connects them to oncogenic RAS (Fig 4c).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [140]
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Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma
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Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors
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Self-citationThe p53 Pathway in Glioblastoma
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Metadata
- Authors
- Wakimoto, H., Tanaka, S., Curry, W. T., Loebel, F., Zhao, D., Tateishi, K., Chen, J., Klofas, L. K., Lelic, N., Kim, J. C., Dias-Santagata, D., Ellisen, L. W., Borger, D. R., Fendt, S.-M., Vander Heiden, M. G., Batchelor, T. T., Iafrate, A. J., Cahill, D. P., & Chi, A. S.
- Affiliations
- Harvard University (US)
- Authors' Affiliations: 1Department of Neurosurgery; 2Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, 3Translational Research Laboratory; 4Department of Pathology; 5Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; 6Translational Neuro-Oncology Laboratory; 7Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; 8Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium
- Corresponding author
- Cahill, Daniel P.
- Chi, Andrew S.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2014-05-29
- Volume
- 20
- Issue
- 11
- Pages
- 2898-2909
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4070445
- OpenAlex
- W2137361994
- Cited by
- 190
- References
- 51
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 16 · 2023: 12 · 2022: 10 · 2021: 22 · 2020: 27 · 2019: 19 · 2018: 18 · 2017: 15 · 2016: 9 · 2015: 15 · 2014: 3
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Funders
- Wellcome Trust
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Cancer Institute (K24CA125440, P50CA165962)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- IDH-mutant glioma, IDH1 mutation, CIC mutation, TP53 mutation, PIK3CA mutation, KRAS mutation, PDGFRA amplification, MET amplification, MYCN amplification, 2-hydroxyglutarate, tumor xenografts, cancer driver mutations, targeted therapy, progression-free survival, oligodendroglioma, astrocytoma
- MeSH terms
- Animals, Brain Neoplasms, Cell Transformation, Neoplastic, Glioma, Humans, Isocitrate Dehydrogenase, Gas Chromatography-Mass Spectrometry, Mutation, Oncogenes, Phenotype, In Situ Hybridization, Fluorescence, Disease-Free Survival, Mice, Kaplan-Meier Estimate, Heterografts
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