TERT promoter mutations and telomere length in adult malignant gliomas and recurrences.

Barbara Heidenreich,Rajiv Kumar,P Sivaramakrishna Rachakonda,Florian Volz,Kari Hemminki,Astrid Weyerbrock,Ismail Hosen

doi:10.18632/oncotarget.3329

Abstract

In this report on 303 gliomas we show the highest frequency of TERT promoter mutations in gliobastomas (80%) followed by oligodendrogliomas (70%) and astrocytomas (39%). We observed positive association between TERT promoter and IDH mutations in oligodendroglial tumors (OR = 26.3; 95% CI 2.5-250.2) and inverse association in primary glioblastomas (OR = 0.13; 95% CI 0.03-0.58). Tumors with TERT promoter mutations compared to those without showed increased TERT transcription; we also showed difference in the transcription levels due to the two main mutations. Tumors with TERT promoter mutations had shorter telomeres than those without. The patients with only TERT promoter mutations showed worst survival (median survival 14.6 months) and patients with both IDH and TERT promoter mutations showed best survival (246.5 months). In patients with astrocytoma, the TERT promoter mutations only associated with poor survival (P < 0.0001); IDH mutations and 1p/19q deletions associated with increased survival (P = 0.0004). TERT promoter mutations in low grade gliomas associated with reduced progression free survival (HR 10.2; 95% CI 1.9 - 55.9). While our data affirm the role of TERT promoter mutations in glial tumors, effects on transcription and telomere length emphasise the importance of telomere biology in disease genesis and outcome.

Highlights

Gliomas are the most common primary malignant brain tumors in adults that mainly arise in glial tissue of the brain
Primary glioblastomas had the highest frequency of telomerase reverse transcriptase (TERT) promoter mutations (132/165; 80%) followed by oligodendrogliomas (19/27; 70%); astrocytomas showed the lowest frequency, with 22 out of 56 (39%) samples showing mutations (Table 1)
TERT promoter mutations were found associated with high grade tumors when compared to lower grade lesions (OR = 3.05; 95% CI 1.79 – 5.19; P < 0.0001; Table 2)

Summary

Introduction

Gliomas are the most common primary malignant brain tumors in adults that mainly arise in glial tissue of the brain. Those tumors are either astrocytic, oligodendrocytic or a mixture of the two cell types and are typically categorized according to the International Classification of Diseases – Oncology, version 3 (ICD-O-3) and World Health Organization (WHO) grade [1, 2]. The most common gliomas are glioblastomas, comprising the two sub-types primary and secondary glioblastoma. The sub-types follow different modes of progression and show distinct genetic alterations [1, 3,4,5]. The majority is constituted by primary glioblastomas and those tumors develop quickly. Glioblastomas exhibit a poor prognosis with a 5-year relative survival of ~5% [1]

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Conclusion