Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas

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=.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 while 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=.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.

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

“…RAS mutations in oligodendrogliomas have not yet been sufficiently researched. [7][8][9][10][11][12][13][14][15] …”

Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas

“…The first is the plausible hypothesis that IDH1-mutant GBMs represent malignant transformation of undiagnosed LGGs, and IDH1 wild-type GBM is, in many ways, a different disease sharing the same histological features. 11,13,37 This theory is supported by studies of serial biopsy samples obtained in patients with glioma, in which the IDH1 mutation appears to be a relatively early genetic event, 11,13,37 preceding other lineage-specific mutations, such as TP53 and ATRX mutations in astrocytomas and 1p19q codeletion, CIC, and telomerase reverse transcriptase (TERT) mutations in oligodendrogliomas. 13,34,37 In The Cancer Genome Atlas studies, IDH1-mutant GBMs cluster by gene expression in the proneural subtype.…”

“…11,13,37 This theory is supported by studies of serial biopsy samples obtained in patients with glioma, in which the IDH1 mutation appears to be a relatively early genetic event, 11,13,37 preceding other lineage-specific mutations, such as TP53 and ATRX mutations in astrocytomas and 1p19q codeletion, CIC, and telomerase reverse transcriptase (TERT) mutations in oligodendrogliomas. 13,34,37 In The Cancer Genome Atlas studies, IDH1-mutant GBMs cluster by gene expression in the proneural subtype. 5,11 The IDH1 mutation initiates a cellular program through the effects of the oncometabolite 2HG, which appears to modulate cellular programs including hypoxia sensing, histone demethylation, and induction of a globally hypermethylated state of DNA and angiogenesis.…”

“…Based on these insights, IDH1 wild-type GBMs are now seen as primary GBMs that probably do not share the same pathophysiological features as secondary GBMs that arise from LGGs with IDH mutation 11 and associated subsequent secondary and tertiary mutations that cause their malignant transformation. 37 Therefore, IDH1 wild-type GBMs behave much differently than their IDH1-mutant counterparts, with a later age of onset, worse prognosis, and distinct imaging characteristics. 13,34,35 A second diagnostic implication of the relationship between tumor grade and IDH status is that LGGs that are IDH wild type clinically tend to behave as aggressively as GBM.…”

“…26 Work with orthotopic xenografts of IDH1-mutated gliomas has identified tertiary alterations, including the PIK-3CA and KRAS mutations as well as PDGFRA, MET, and N-Myc amplification, which appear to be involved in the eventual malignant transformation of LGGs. 37 Retrospective analysis of 149 patients with gliomas showed that tertiary alterations were present in 13.4% of the sample and were found exclusively in high-grade gliomas or progressive LGGs. The development of tertiary alterations after progression in LGGs was associated with significantly shorter subsequent PFS (median 9 vs 36.1 months, p = 0.0011), whereas there was no significant difference in PFS from the time of initial diagnosis.…”