CONFIRMATION OF TERT PROMOTER MUTATION AS A PROGNOSTIC MARKER IN A GREEK COHORT WITH GLIOMA

Introduction: Telomerase reverse transcriptase (TERT) has received a great deal of attention in recent years for its role as a prognostic and predictive molecular marker of glioma. Mutation in the TERT promoter (TERTp mut), which results in enhanced telomerase activity and shortened telomeres, is seen in both the most aggressive human glioma (glioblastoma) and the least aggressive diffuse human glioma (grade II oligodendroglioma). Materials and Methods: We sequenced for TERTp-mut in 48 glioma DNAs and analysed TERT expression by RT-PCR. TERTp-mut status was correlated with histology, genomic profile, other biomarkers and clinical outcome. Results: TERT promoter mutations were observed in 35 out of 48 tumor samples. Of these, C228T (-124 bp upstream start codon) mutation was detected in 28 samples and C250T (-146 bp) mutation in 7 cases. Of the TERT-mutant gliomas, 32 were glioblastomas, one was an anaplastic astrocytoma, one was an anaplastic oligodendroglioma and another one was a grade II oligodendroglioma, IDH mutant and 1p19q co-deleted. TERT promoter mutations have been associated with shorter overall survival in high grade gliomas while a longer survival in low grade tumors (the small number of low grade gliomas in our cohort is not representative). The median overall survival was 11 months for C228T mutated gliomas and 6 months for C250T mutated, while the overall survival was 13 months for the TERT wild-type gliomas. We defined four prognostic groups, based on TERTp-mut and IDH mutation status: (1) TERTp-mut and IDH-mut (3 patients) associated with 1p19q codeletion, with overall survival 10 months (because of the small number of patients tested until now, the results in this subgroup are not reliable); (2) TERTp-wt and IDH-mut (4 patients), with overall survival 31 months; (3) TERTp-wt and IDH-wt (9 patients), with overall survival 13 months; (4) TERTp-mut and IDH-wt (32 patients), with overall survival 12 months. The 5 out of 6 EGFRvIII gliomas were found to belong in the fourth group, with a median overall survival 20 months. CONCLUSION: The presence or absence of TERT promoter mutations, IDH mutations, and 1p/19q co-deletion can be used to define four principal groups of gliomas with characteristic distributions of age at diagnosis, clinical behavior, acquired genetic alterations, and other biomarkers. In our cohort, the poor prognosis of TERT- mutated high grade gliomas is confirmed, while in the low grade the sample is not representative. Further analysis of TERTp-mut in more samples is pending, as is its association with other biomarkers, clinical characteristics and treatment.