Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas

Abstract

Background Children with high-grade glioma, including diffuse intrinsic pontine glioma (DIPG), have a poor prognosis despite multimodal therapy. Identifying novel therapeutic targets is critical to improve their outcome. We evaluated prognostic roles of telomere maintenance mechanisms in children with HGG, including DIPG. Methods A multi-institutional retrospective study was conducted involving 50 flash-frozen HGG (35 non-brainstem; 15 DIPG) tumors from 45 children (30 non-brainstem; 15 DIPG). Telomerase activity, expression of hTERT mRNA (encoding telomerase catalytic component) and TERC (telomerase RNA template) and alternative lengthening of telomeres (ALT) mechanism were assayed. Cox Proportional Hazard regression analyses assessed association of clinical and pathological variables, TERC and hTERT levels, telomerase activity, and ALT use with progression-free or overall survival (OS). Results High TERC and hTERT expression was detected in 13/28 non-brainstem HGG samples as compared to non-neoplastic controls. High TERC and hTERT expression was identified in 13/15 and 11/15 DIPG samples, respectively, compared to controls. Evidence of ALT was noted in 3/11 DIPG and 10/19 non-brainstem HGG specimens. ALT and telomerase use were identified in 4/19 non-brainstem HGG and 2/11 DIPG specimens. In multivariable analyses, increased TERC and hTERT levels were associated with worse OS in patients with non-brainstem HGG, after controlling for tumor grade or resection extent. Conclusions Children with HGG and DIPG, have increased hTERT and TERC expression. In children with non-brainstem HGG, increased TERC and hTERT expression levels are associated with a worse OS, making telomerase a promising potential therapeutic target in pediatric HGG.

Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors

“…We have previously shown that over 73% of DIPG and 50% of high-grade gliomas (HGG; ref. 10) demonstrate telomerase activity. We recently conducted a molecular biology and phase II study of imetelstat, a potent inhibitor of telomerase (11,12), to estimate inhibition of tumor telomerase activity and efficacy in children with recurrent central nervous system (CNS) malignancies (13).…”

A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study

“…Telomerase activity has been detected in 10–100% of anaplastic astrocytomas [3, 4], 26–100% of glioblastoma [4] and 60–86% of ependymomas[5, 6]. High hTERT expression occurs in up to 76% of medulloblastoma/supratentorial primitive neuroectodermal tumors (PNET) [7] and 73% of diffuse intrinsic pontine gliomas (DIPG) [8]. Telomerase activation is a negative prognosticator across CNS tumors [9, 8, 5] and may play a role in cancer stemness [10, 5, 11], making telomerase inhibition a rational therapeutic target even in the setting of cancer recurrence and therapy resistance.…”

Association of Telomerase Reverse Transcriptase Promoter Mutations with the Prognosis of Glioma Patients: a Meta-Analysis

“…Previous studies also found that the occurrence of TERT promoter mutations in gliomas was frequent [6,10,11]. So far, several studies on the association between TERT promoter mutations and prognosis of gliomas had been performed, but the conclusion still was not uncertain [6,[12][13][14][15][16]. The aim of the present meta-analysis was to assess the association between TERT promoter mutations and survival of glioma patients by pooling data from published studies.…”