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

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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.

ABBREVIATIONS 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; pGBM = primary GBM; PTEN = phosphatase and tensin homolog; TERTp-mut = telomerase promoter mutations; wt = wild type.

Article Information

Correspondence Koray Özduman, Acıbadem University School of Medicine, Department of Neurosurgery, Inonu Cad. Okur Sok. No. 20 Kozyatagi, Istanbul 34742, Turkey. email: koray.ozduman@icloud.com.

INCLUDE WHEN CITING Published online June 16, 2017; DOI: 10.3171/2016.11.JNS16973.

Disclosures Dr. von Deimling is a patent holder in Ventana/Roche and DIANOVA.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    A: In 356 tumors, no exclusive association between the histopathological diagnosis and TERTp-mut status was noted. B: The C228T hotspot was approximately twice as common as C250T. C: No TERTp-mut were detected in the peritumoral brain parenchyma. C and D: TERTp-mut tumors tended to be more anaplastic, and the patients tended to be older. E: These findings do not indicate an accumulation of TERT mutations over time, because the initial mutational status remained stable at all recurrences over long follow-up periods despite malignant degeneration and administration of mutagenic adjuvant therapies such as temozolomide and radiation. chemo = chemotherapy.

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    A: A discrepancy between the histopathological diagnosis and oncogenic signatures was found. Even in oligodendroglioma, WHO Grade II, only two-thirds of the patients carried the “prototypic” IDH mutations and 1p/19q codeletions. B and C: TERTp-mut separated at least 2 oncogenic signatures in oligodendrogliomas, astrocytomas, and mixed tumors of all grades. D: IDH-wt WHO Grade II and III gliomas also exhibited oncogenic signatures similar to those of primary GBMs.

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    When we remain blinded to histopathology results, the combination of IDH-mut and TERTp-mut status defines 4 molecular subsets. A: Relative incidences of these molecular subsets vary according to tumor grade. B: IDH-wt gliomas display mostly anaplastic features, whereas IDH-mut gliomas are predominantly lower grade at presentation. The incidence of IDH-mut peaks at younger patient ages. C: The incidence of TERT-only cases increases with age, whereas that of double-negative cases remains relatively constant over time.

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    The anatomical distribution of each molecular subset followed a unique pattern. The frontal lobe was the most common site for all molecular groups. The double-mutant subset had a very strong predilection for the frontal lobe. At the insula, a strong predilection for IDH-only tumors was found. IDH-mut tumors were encountered infrequently in the parietal and occipital lobes. Multifocality was observed only in the TERT-only and IDH-only subsets.

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    Each of the 4 molecular subsets has distinct clinical characteristics. A: Regardless of the molecular subset, patients with a WHO Grade IV tumor at initial presentation were significantly older than those with a lower-grade tumor. Patients of the TERT-only subset were also significantly older at lower tumor grades than patients with tumors of the same grade of different subsets. B: These patients with a WHO Grade II or III tumor also exhibited higher proliferative indexes compared to those of other subsets. C–F: The TERT-only subset was associated with poorer prognosis than all subgroups at all WHO grades. The double-negative subset contained young patients with a low proliferative index and good survival at WHO Grade II and older patients with a high proliferative index and poor survival at higher tumor grades (A, B, D, E, and F). These results hint at further subgroups in this molecular subset. IDH-mut gliomas were associated with a much better prognosis than IDH-wt HDGs (C, D, E, and F). Mean values are presented at the center of the columns. Error bars indicate the standard error. Significant results are marked with stars, and the p values are indicated.

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    Unsupervised CART analysis based on overall survival was performed with data from 299 unique patients. 1p/19q codeletion and p53 statuses were identified as significant indicators in IDH-mut tumors. One should consider that in this cohort, all 1p/19q-codeleted tumors also included TERTp-mut and that 96.3% of patients in the double-mutant subset carried the 1p/19q codeletion. Compared with IDH-mut status, the predictive power of each of the significant variables is small but significant, as indicated by the “normalized importance.”

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    The same unsupervised CART analysis based on overall survival analysis, as shown in Fig. 6, was performed with patient age and WHO grade as covariates and yielded very similar findings.

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    This heatmap plots the IDH, TERT, H3.3, and ATRX mutational statuses against most common tyrosine-kinase receptor pathway changes (PTEN, EGFR, and PDGFRA) and key cell-cycle regulators (CDKN2A, CDK4, and RB1) in 68 patients with HDGs. WHO group, WHO grade, TP53 and Ki-67 index statuses, age, and survival data were also included to create a more comprehensive picture. IDH-mut tumors had few tyrosine-kinase or cell-cycle regulator changes. No EGFR, PDGFR, or PTEN mutations were observed in IDH-mut tumors. Only EGFR amplification events were observed in IDH-mut tumors, and they were in the IDH-only subset. The TERT-only subset had the highest incidences of EGFR, PTEN, and cell-cycle regulator changes. At least 4 oncogenic profiles were noted in the double-negative group, which consisted of an ATRX-mut profile that resulted in good overall survival, an ATRX-mut and H3.3 mutant profile that resulted in extremely poor survival, an ATRX-mut profile with receptor tyrosine kinase and PTEN changes that resulted in poor survival, and an ATRX wild-type profile that again resulted in poor survival. This heatmap is meant to be seen as a proof of principle for the fact that the 4 molecular subsets carry different oncogenic profiles, but it does not show a comprehensive analysis. A = astrocytoma; G = IDH1-R132G mutation present; G34 = H3.3-G34V mutation present; H = IDH1-R132H mutation present; HE = heterozygous deletion; HO = homozygous deletion; N/A = not available; OA = oligoastrocytoma; OD = oligodendroglioma; ONC = Affymetrix-OncoScan analysis; MSM = microsatellite marker analysis; NGS = next-generation sequencing; S = IDH1-R132S mutation present; SNG = Sanger sequencing; xN = low-level amplification; XN = high-level amplification.

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