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TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations.

Abstract：

BACKGROUND:The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter. METHODS:We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. RESULTS:TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation. CONCLUSIONS:In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Labussière M,Di Stefano AL,Gleize V,Boisselier B,Giry M,Mangesius S,Bruno A,Paterra R,Marie Y,Rahimian A,Finocchiaro G,Houlston RS,Hoang-Xuan K,Idbaih A,Delattre JY,Mokhtari K,Sanson M

doi

10.1038/bjc.2014.538

subject

Has Abstract

pub_date

2014-11-11 00:00:00

pages

2024-32

issue

eissn

0007-0920

issn

1532-1827

pii

bjc2014538

journal_volume

111

pub_type

杂志文章

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TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations.