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Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas

Hiroaki Wakimoto1, Shota Tanaka1, William T Curry2

  • 1Authors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, BelgiumAuthors' Affiliations: Department of Neurosurgery; Division of Hematology/Oncology, Department of Neurology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Translational Research Laboratory; Department of Pathology; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge; Translational Neuro-Oncology Laboratory; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Vesalius Research Center, VIB and Department of Oncology, KU Leuven, Leuven, Belgium.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 10, 2014
PubMed
Abstract

Insights

Certain IDH-mutant gliomas with additional driver mutations show a more aggressive cancer phenotype. Identifying these genetic alterations may guide targeted therapy for improved patient outcomes.

Area of Science:

  • Neuro-oncology
  • Cancer Genomics
  • Molecular Pathology

Background:

  • Isocitrate dehydrogenase (IDH) gene mutations are prevalent in both low-grade and high-grade gliomas.
  • Understanding the genetic drivers of malignant phenotype heterogeneity in IDH-mutant gliomas is crucial for effective treatment strategies.

Purpose of the Study:

  • To identify the genetic basis for the diverse malignant phenotypes observed in IDH-mutant gliomas.
  • To investigate the role of additional genetic alterations in driving glioma progression and heterogeneity.

Main Methods:

  • Prospective implantation of 20 IDH1-mutant glioma specimens into mouse brains for xenograft development.
  • Comprehensive genotyping of tumor specimens using a CLIA-certified molecular panel.
  • In vitro testing of gliomas with driver mutations for sensitivity to targeted inhibitors and analysis of genomic alterations and patient outcomes.

Main Results:

  • Eight of 20 IDH1-mutant gliomas formed intracerebral xenografts, maintaining mutant IDH1 and high 2-hydroxyglutarate levels.
  • Xenograft-forming gliomas frequently harbored lineage-defining mutations (CIC or TP53) plus additional driver mutations (PIK3CA, PDGFRA, MET, N-MYC), unlike non-xenograft-forming gliomas.
  • Driver alterations were found in 13.4% of IDH-mutant glioma patients, correlating with specific mutation patterns (IDH/CIC with PIK3CA/KRAS; IDH/TP53 with PDGFRA/MET amplification).
  • The presence of driver alterations at progression was linked to significantly shorter progression-free survival (9.0 vs. 36.1 months).

Conclusions:

  • A subset of IDH-mutant gliomas exhibits a more malignant phenotype due to mutations in driver oncogenes.
  • Identifying these specific genetic alterations offers potential for targeted therapy in affected glioma patients.
  • These findings highlight the importance of comprehensive genomic profiling for personalized glioma treatment.

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