IDH Mutation and Neuroglial Developmental Features Define Clinically Distinct Subclasses of Lower Grade Diffuse Astrocytic Glioma
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Clinical Cancer Research
(Impact Factor: 8.72).
03/2012; 18(9):2490-501. DOI: 10.1158/1078-0432.CCR-11-2977
Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma [World Health Organization (WHO) IV], its most malignant subtype, lower grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notable clinical heterogeneity. Accordingly, we sought to identify and characterize clinically relevant molecular subclasses of lower grade diffuse astrocytic gliomas.
We conducted multidimensional molecular profiling, including global transcriptional analysis, on 101 lower grade diffuse astrocytic gliomas collected at our own institution and validated our findings using publically available gene expression and copy number data from large independent patient cohorts.
We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, platelet-derived growth factor receptor (PDGFR)A overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone. This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors.
We have elucidated molecularly distinct subclasses of lower grade diffuse astrocytic glioma that dictate clinical behavior and show fundamental associations with both IDH mutational status and neuroglial developmental stage.
Available from: Xing Liu
- "Over the past 30 years, recurrent chromosomal, cell biological, and genetic alterations have implicated a number of molecules in the different histological types and malignancy grades of astrocytic tumors . Recently, various molecular markers have been reported to correlate with an improved group of adult gliomas. "
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ABSTRACT: Astrocytic tumors are the most common primary brain tumors in adults. ATRX mutations have been identified in gliomas and are correlated with its loss of expression, which causes alternative lengthening of telomeres (ALT) leading to genomic instability. In this study, we aimed to explore the role of ATRX mRNA expression alteration in the progression and subclassification of astrocytic tumors and examine its impact on clinical outcome. We investigated ATRX mRNA expression and its association with IDH1 and IDH2 mutations in 169 adult astrocytic tumors using whole transcriptome sequencing. In our cohort, low ATRX mRNA expression was detected in 68% of astrocytomas, 50% of anaplastic astrocytomas and 41.6% of glioblastomas. Low ATRX expression closely overlapped with mutations in IDH1/2 (P<0.0001) in astrocytic tumors across WHO grades II-IV. Significant association between low ATRX expression and longer overall survival was identified in our cohort (P<0.01). ATRX combined with IDH1/2 and Ki-67 was used to re-classify patients with astrocytic tumors: group A1 containing IDH1/2 mutations and low ATRX expression predicted a better prognostic outcome, whereas group A3 carrying wild-type IDH1/2 and high Ki-67 expression had the shortest overall survival; IDH-mutant tumors with low ATRX expression and IDH-wild-type tumors with high Ki-67 expression were grouped into group A2. In summary, our results showed that ATRX in cooperation with IDH1/2 and Ki-67 defines three subgroups of astrocytic tumors regardless of the conventional WHO grades consensus. The molecular stratification in astrocytic tumors may aid in treatment strategy selection, therapeutic trial design, and clinical prognosis evaluation.
Available from: Marta Mellai
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ABSTRACT: Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, non-comparative, phase II study of radiation (RT) and temozolomide (TMZ) with or without vandetanib in patients with newly diagnosed glioblastoma (GBM).
We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and TMZ with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis.
The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 pts (36 in the RT/TMZ arm, 70 in the vandetanib/RT/TMZ arm). Median OS was 15.9 months [95% CI, 11.0 months, 22.5 months] in the RT/TMZ arm and 16.6 months [95% CI, 14.9 months, 20.1 months] in the vandetanib/RT/TMZ (log-rank p=0.75).
The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or GS was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong overall survival compared to the parallel control arm, leading to early termination of the study.
Copyright © 2015, American Association for Cancer Research.
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