Abstract
Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNP's, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.
Highlights
Gliomas are the most common malignant brain tumors, where in adults primary glioblastoma (GBM) is the most aggressive
Interleukin-6 (IL-6) expression regulated by Telomerase reverse transcriptase (TERT) promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival
We report a significant association of certain TERT SNPs with risk of developing glioblastoma
Summary
Gliomas are the most common malignant brain tumors, where in adults primary glioblastoma (GBM) is the most aggressive. C228T and C250T located at –124 and –146 pb upstream from the ATG start site confer enhanced TERT promoter activity, by putatively generating consensus binding sites (GGAA) for ETS transcription factors within the TERT promoter region [8, 9]. These mutational hot spots are most frequently found in primary glioblastomas (82%) and oligodendrogliomas (78%), but are less common in secondary glioblastomas (35%) [10, 11]. TERT rs2853669 has been shown to modulate both TERT expression and impact on prognosis in bladder cancer and GBM [13, 14]
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