gms | German Medical Science

Objective: Telomerase reverse transcriptase (hTERT), the catalytic component of telomerase, was previously shown to be over-expressed in gliomas. In many cases, this is related to hTERT promoter mutations (C228T and C250T).This study aimed at identification of oncogenic processes associated with the expression of hTERT in gliomas and its effects on patient outcome.

Method: In the present study, a total of 134 glioma tumor samples [59 oligodendrogliomas (46 grade II and 13 grade III), 20 oligoastrocytomas (10 grade II and 10 grade III), 18 astrocytomas (10 grade II and 8 grade III), 35 glioblastomas, and 2 gliomatosis cases] were screened for hTERT promoter mutations. Findings were correlated with IDH, Olig-2, Ki67, EGFR, VEGF, pBRAF, c-myc PTEN, p16 protein expressions and MGMT methylation, 1p19q co-deletions and copy number variations. In order to screen the effects of hTERT expression on the proteome, 8 hTERT promoter mutant and 2 wild-type WHO grade II oligodendrogliomas were compared using LC-MS/MS. Overall survival as well as progression free survival was also correlated with hTERT promoter mutations.

Results: hTERT promoter mutations were detected in 56% (75/134) of gliomas analyzed. Relative incidence of promoter mutations was 71.7 in oligodendroglioma grade II, 77% in oligodendroglioma grade III, 10% in oligoastrocytoma grade II, 60% in oligoastrocytoma grade III, 10% in astrocytoma grade II, 12.5% in astrocytoma grade III and 60% in glioblastomas. In oligodendrogliomas, hTERT promoter mutations were correlated with higher incidence of IDH mutations, higher incidence of 1p19q co-deletions and lower incidence of p53 mutations. There were no differences in tumor localization, laterality, overall- or progression free- survival. With LC-MS/MS analysis, a total of 1606 proteins were identified (false discovery rate of 0.2%). 75 of these proteins were significantly differentially expressed in the hTERT gliomas (p<0.05). 11 of the proteins had been associated with glioma development previously. Pathway analysis revealed involvement of transcriptional silencing, cell cycle and cell-adhesion.

Conclusions: The hTERT promoter mutations are correlated with higher incidence of IDH mutations, 1p19q co-deletions and lower incidence of p53 mutations in oligodendrogliomas. The proteomic analysis suggested the involvement of important pathways. The presence of hTERT mutations may point to a different oncogenic program in oligodendrogliomas.