TERT Promoter Mutations Lead to High Transcriptional Activity under Hypoxia and Temozolomide Treatment and Predict Poor Prognosis in Gliomas

Chen Chen,Sheng Han,Marta M. Alonso,Lingxuan Meng,Anhua Wu,Xue Zhang,Zhonghua Li

doi:10.1371/journal.pone.0100297

Abstract

ObjectiveThis study explored the effects of telomerase reverse transcriptase (TERT) promoter mutations on transcriptional activity of the TERT gene under hypoxic and temozolomide (TMZ) treatment conditions, and investigated the status and prognostic value of these mutations in gliomas.MethodsThe effect of TERT promoter mutations on the transcriptional activity of the TERT gene under hypoxic and TMZ treatment conditions was investigated in glioma cells using the luciferase assay. TERT promoter mutations were detected in 101 glioma samples (grades I–IV) and 49 other brain tumors by sequencing. TERT mRNA expression in gliomas was examined by real-time PCR. Hazard ratios from survival analysis of glioma patients were determined relative to the presence of TERT promoter mutations.ResultsMutations in the TERT promoter enhanced gene transcription even under hypoxic and TMZ treatment conditions, inducing upregulation of TERT mRNA expression. Mutations were detected in gliomas, but not in meningiomas, pituitary adenomas, cavernomas, intracranial metastases, normal brain tissues, or peripheral blood of glioma patients. Patients with TERT promoter mutations had lower survival rates, even after adjusting for other known or potential risk factors, and the incidence of mutation was correlated with patient age.Conclusion TERT promoter mutations were specific to gliomas. TERT promoter mutations maintained its ability of inducing high transcriptional activity even under hypoxic and TMZ treatment conditions, and the presence of mutations was associated with poor prognosis in glioma patients. These findings demonstrate that TERT promoter mutations are novel prognostic markers for gliomas that can inform prospective therapeutic strategies.

Highlights

The telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase, which is normally not expressed by postmitotic somatic cells
TERT Promoter Mutations are Associated with Gliomas Among 152 tumor samples, TERT promoter mutations were found only in gliomas, and not in meningiomas, pituitary adenomas, cavernomas, intracranial metastases, normal brain tissues, or in peripheral blood samples (Fig. 1A)
TERT promoter mutations were significantly associated with patient age (P = 0.004)

Summary

Introduction

The telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase, which is normally not expressed by postmitotic somatic cells. Mutations in the TERT promoter that create a novel binding site for T-cell factor (TCF) transcription factors, thereby increasing TERT gene transcription, have been identified in cutaneous melanoma. Individuals with these mutations have increased cancer susceptibility, as demonstrated in studies of familial melanoma [2,3]. TCF transcription factors have important roles in developing and adult brains [4,5,6,7] as the main effectors of the canonical Wnt/bcatenin signaling pathway, which is dysregulated in various types of cancers [8]. We hypothesized that some pathological molecular changes leading to constant abnormal expression of mitosis related genes may contribute to the poor prognosis. The effect of TERT promoter mutations was examined in glioma cells, and the mutation status of the promoter was analyzed in glioma patients with respect to glioma progression and patient survival

Methods

Results

Conclusion