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

Background: The role of telomerase reverse transcriptase ( TERT ) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations ( TERT p-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 TERT p-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERT p-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. Results: TERT p-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 TERT p-mut and IDH mutation status, four prognostic groups: (1) TERT p-mut and IDH -mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERT p-wt and IDH -mut, associated with TP53 mutation, OS=97.5 months; (3) TERT p-wt and IDH -wt, with no specific association, OS=31.6 months; (4) TERT p-mut and IDH -wt, associated with EGFR amplification, OS=15.4 months. TERT p-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 TERT p-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERT p-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.