TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma

// Mohamed Ali Mosrati 1 , Annika Malmstrom 2 , Malgorzata Lysiak 1 , Adam Krysztofiak 1 , Martin Hallbeck 3 , Peter Milos 4 , Anna-Lotta Hallbeck 5 , Charlotte Bratthall 6 , Michael Strandeus 7 , Marie Stenmark-Askmalm 8 , Peter Soderkvist 1 1 Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden 2 Department of Advanced Home Care and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden 3 Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden 4 Department of Neurosurgery and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden 5 Department of Oncology and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden 6 Department of Oncology, District Hospital, Kalmar, Sweden 7 Department of Oncology, Ryhov Hospital, Jonkoping, Sweden 8 Department of Clinical Pathology and Clinical Genetics and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, 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.