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

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.

TERT Promoter Alterations in Glioblastoma: A Systematic Review

“…Whether TERTp mutation status is an independent prognostic factor is highly controversial. Numerous studies have highlighted the potential negative independent prognostic impact of TERTp mutations [ 18 , 19 , 20 , 21 , 24 , 25 , 61 , 62 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ], whereas others [ 14 , 17 , 51 , 53 , 56 , 63 , 64 , 65 , 75 , 76 ] have suggested that the deleterious impact of TERTp mutation is correlated to the presence of cofounding molecular and clinical factors such as older age, IDH-wt status, and unmethylated MGMTp status. The MGMT gene codes for a protein involved in the DNA repair system.…”

A comprehensive DNA panel next generation sequencing approach supporting diagnostics and therapy prediction in neurooncology

“…This would be a rather unusual molecular constellation for pilocytic astrocytoma. Instead, combined mutations in TERTp , PTEN and NF1 are described for high-grade gliomas and are associated with an unfavorable prognosis [ 35 , 36 ]. Not surprisingly, this patient suffered from tumor progression at already 9 months after the first surgery, despite gross total resection.…”

The Era of Radiogenomics in Precision Medicine: An Emerging Approach to Support Diagnosis, Treatment Decisions, and Prognostication in Oncology

“…These two genes play a critical role in the progression of GBM. It has been shown that mutations of NF1 , a tumor suppressor gene, are quite common in the mesenchymal molecular subtype, which has a very poor prognosis due to aggressive biological behavior ( 60 , 74 ). Patients with GBM who have an activated phosphatidylinositol 3-kinase (PI3K) signaling pathway also have poorer outcomes than those who do not ( 75 ).…”