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. 2020 Feb;13(2):346-354.
doi: 10.1016/j.tranon.2019.10.016. Epub 2019 Dec 28.

Is There an Independent Role of TERT and NF1 in High Grade Gliomas?

Evangelia Razis  1 , Vassiliki Kotoula  2 , Georgia-Angeliki Koliou  3 , Kyriaki Papadopoulou  4 , Eleni Vrettou  5 , Eleni Giannoulatou  6 , Ioannis Tikas  4 , Stefanos V Labropoulos  7 , Georgios Rigakos  7 , Styliani Papaemmanoyil  8 , Ourania Romanidou  9 , Eugenia Bourkoula  10 , Panagiotis Nomikos  11 , Georgios Iliadis  12 , George Nasioulas  10 , Panagiotis Selviaridis  13 , Konstantinos Polyzoidis  13 , George Fountzilas  14
Affiliations

Is There an Independent Role of TERT and NF1 in High Grade Gliomas?

Evangelia Razis et al. Transl Oncol. 2020 Feb.

Abstract

Background: High grade glioma molecular profiling is of particular interest in neurooncology. The role of telomerase reverse transcriptase (TERT) varies dependent upon other molecular parameters. We explored the role of TERT in 101 high-grade gliomas.

Methods: A total of 101 patients (pts) with grade III-IV gliomas treated with standard of care and informative tumor genotypes were included in the present study. Of 55 genes targeted with the next-generation sequencing panel, mutations (muts) were found in 37; these were included in the analysis. TERT mut were tested with Sanger sequencing. MGMT promoter methylation status was determined by methylation specific PCR.

Results: 270 mut were detected in 92/101 tumors (91.1%). TERT was the most frequently mutated gene (74.3%). IDH1/2 mut were mutually exclusive with mut in the neurofibromin 1 (NF1) gene. Mutated TERT was associated with wild-type (wt) IDH1/2 (p = 0.025). The 12-month overall survival (OS) rate was 74.3% (median OS: 22 months). Pts with TERT and NF1 wt had a median OS of 40.8 months, while among pts with NF1 wt/TERT mutant, the median OS was 18.5 months. NF1 and TERT mut univariately conferred shorter OS (HR = 3.19; p = 0.004 and HR = 2.28; p = 0.002). Upon multivariate analysis, mutated TERT showed marginal unfavorable prognostic significance for OS (p = 0.049), while NF1 lost its unfavorable significance (p = 0.151).

Conclusions: TERT is herein proven to confer poor prognosis in high grade gliomas, independent of IDH and MGMT. NF1 seems to also confer poor prognosis although our small numbers do not allow for firm conclusions.

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Figures

Figure 1
Figure 1
REMARK diagram.
Figure 2
Figure 2
Maps show the distribution of mutations per gene per tumor.A.Mutation profiles for all affected genes.B.Mutual exclusiveness of NF1 and IDH1/2 mutations and their association with TERT mutations. Of the seven tumors with NF1 mutations, 4 (beige bars) had frame shift deletions: p.Tyr2285fs at 57% frequency of the tumor DNA at this position, p.Asp2346fs at 68%, p.Phe1247fs at 80%, and p.Pro678fs at 28%; 2 tumors (purple bar) had nonsense mutations: p.Gln2302Ter at 16% and p.Gln1255Ter at 18% frequency; lastly, one tumor (blue bar) had two missense mutations (p.Gly1133Asp, p.Val1146Ile) at 20% and 30% frequency of the tumor DNA; the latter was the only NF1 mutated tumor without mutated TERT.
Figure 3
Figure 3
Kaplan–Meier plots with respect to overall survival based on the mutational status of (A) NF1, (B) TERT, and (C) IDH1/2 genes in the entire cohort and (D) TERT/NF1 among patients with IDH1/2 wild-type tumors.
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