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Clin Cancer Res. 2014 Jun 1;20(11):2898-909. doi: 10.1158/1078-0432.CCR-13-3052. Epub 2014 Apr 8.

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

Author information

1
Authors' 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.
2
Authors' 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.
3
Authors' 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.
4
Authors' 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 chi.andrew@mgh.harvard.edu cahill@mgh.harvard.edu.

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.

PMID:
24714777
PMCID:
PMC4070445
DOI:
10.1158/1078-0432.CCR-13-3052
[Indexed for MEDLINE]
Free PMC Article
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