TERT promoter mutations lead to high transcriptional activity under hypoxia and temozolomide treatment and predict poor prognosis in gliomas

PLoS One. 2014 Jun 17;9(6):e100297. doi: 10.1371/journal.pone.0100297. eCollection 2014.

Abstract

Objective: This 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.

Methods: The 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.

Results: Mutations 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / pharmacology
  • Biomarkers, Tumor / genetics
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics
  • Brain Neoplasms / mortality
  • Brain Neoplasms / secondary
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glioma / drug therapy*
  • Glioma / genetics
  • Glioma / mortality
  • Glioma / pathology
  • Humans
  • Hypoxia / physiopathology*
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Staging
  • Prognosis
  • Promoter Regions, Genetic / genetics*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Telomerase / genetics*
  • Temozolomide

Substances

  • Antineoplastic Agents, Alkylating
  • Biomarkers, Tumor
  • RNA, Messenger
  • Dacarbazine
  • TERT protein, human
  • Telomerase
  • Temozolomide