Oncotarget

Clinical Research Papers:

TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma

Mohamed Ali Mosrati _, Annika Malmström, Malgorzata Lysiak, Adam Krysztofiak, Martin Hallbeck, Peter Milos, Anna-Lotta Hallbeck, Charlotte Bratthäll, Michael Strandéus, Marie Stenmark-Askmalm and Peter Söderkvist

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Oncotarget. 2015; 6:16663-16673. https://doi.org/10.18632/oncotarget.4389

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Abstract

Mohamed Ali Mosrati1, Annika Malmström2, Malgorzata Lysiak1, Adam Krysztofiak1, Martin Hallbeck3, Peter Milos4, Anna-Lotta Hallbeck5, Charlotte Bratthäll6, Michael Strandéus7, Marie Stenmark-Askmalm8, Peter Söderkvist1

1Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

2Department of Advanced Home Care and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

3Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

4Department of Neurosurgery and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

5Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

6Department of Oncology, District Hospital, Kalmar, Sweden

7Department of Oncology, Ryhov Hospital, Jönköping, Sweden

8Department of Clinical Pathology and Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

Correspondence to:

Mohamed Ali Mosrati, e-mail: mohamed.ali.mosrati@liu.se

Keywords: TERT polymorphism, TERT promoter mutations, IDH1 mutation, glioblastoma, IL-6

Received: March 26, 2015     Accepted: June 12, 2015     Published: June 22, 2015

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.


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