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J Neurosurg. 2018 Apr;128(4):1102-1114. doi: 10.3171/2016.11.JNS16973. Epub 2017 Jun 16.

Use of telomerase promoter mutations to mark specific molecular subsets with reciprocal clinical behavior in IDH mutant and IDH wild-type diffuse gliomas.

Author information

1
Departments of1Medical Biology.
2
2Department of Medical Engineering, Faculty of Engineering; and.
3
3Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut.
4
4Medical Statistics and Bioinformatics.
5
5Neurosurgery.
6
6Medical Biochemistry, and.
7
9Pathology, School of Medicine.
8
7Department of Neuropathology, Heidelberg University; and.
9
8German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Clinical Cooperation Unit (CCU) Neuropathology, Heidelberg, Germany.
10
10Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Acıbadem University, Istanbul, Turkey.

Abstract

OBJECTIVE Recent studies have established that hemispheric diffuse gliomas may be grouped into subsets on the basis of molecular markers; these subsets are loosely correlated with the histopathological diagnosis but are strong predictors of clinical tumor behavior. Based on an analysis of molecular and clinical parameters, the authors hypothesized that mutations of the telomerase promoter (TERTp-mut) mark separate oncogenic programs among isocitrate dehydrogenase 1 and/or 2 (IDH) mutant (IDH-mut) and IDH wild-type (IDH-wt) diffuse gliomas independent of histopathology or WHO grade. METHODS Four molecular subsets of the combined statuses of IDH and TERT-promoter mutations (double mutant, IDH only, TERT only, and double negative) were defined. Differences in age, anatomical location, molecular genetics, and survival rates in a surgical cohort of 299 patients with a total of 356 hemispheric diffuse gliomas (WHO Grade II, III, or IV) were analyzed. RESULTS TERTp-mut were present in 38.8% of IDH-mut and 70.2% of IDH-wt gliomas. The mutational status was stable in each patient at 57 recurrence events over a 2645-month cumulative follow-up period. Among patients with IDH-mut gliomas, those in the double-mutant subset had better survival and a lower incidence of malignant degeneration than those in the IDH-only subset. Of patients in the double-mutant subset, 96.3% were also positive for 1p/19q codeletions. All patients with 1p/19q codeletions had TERTp-mut. In patients with IDH-mut glioma, epidermal growth factor receptor or phosphatase and tensin homolog mutations were not observed, and copy-number variations were uncommon. Among IDH-wt gliomas, the TERT-only subset was associated with significantly higher age, higher Ki-67 labeling index, primary glioblastoma-specific oncogenic changes, and poor survival. The double-negative subset was genetically and biologically heterogeneous. Survival analyses (Kaplan-Meier, multivariate, and regression-tree analyses) confirmed that patients in the 4 molecular subsets had distinct prognoses. CONCLUSIONS Molecular subsets result in different tumor biology and clinical behaviors in hemispheric diffuse gliomas.

KEYWORDS:

ATRX-mut = ATRX mutations; CART = classification and regression tree; EGFR = epidermal growth factor receptor; GBM = glioblastoma; H3F3A-mut = H3 histone family member 3A mutations; HDG = hemispheric diffuse glioma; IDH = isocitrate dehydrogenase 1 and/or 2; IDH-mut = IDH mutations; IHC = immunohistochemistry; MLPA = multiplex ligation-dependent probe amplification; PDGFR = platelet-derived growth factor receptor; PTEN = phosphatase and tensin homolog; TERTp-mut = telomerase promoter mutations; glioma; isocitrate dehydrogenase; mutation; oncology; pGBM = primary GBM; prognosis; telomerase; wt = wild type

PMID:
28621624
DOI:
10.3171/2016.11.JNS16973

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