title: TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma.
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.
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Mohamed Ali
authors.initials: MA
authors.lastname: Mosrati
authors.affiliation: Department of Advanced Home Care and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Malmström
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Lysiak
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Krysztofiak
authors.affiliation: Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Hallbeck
authors.affiliation: Department of Neurosurgery and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Milos
authors.affiliation: Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Anna-Lotta
authors.initials: AL
authors.lastname: Hallbeck
authors.affiliation: Department of Oncology, District Hospital, Kalmar, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bratthäll
authors.affiliation: Department of Oncology, Ryhov Hospital, Jönköping, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Strandéus
authors.affiliation: Department of Clinical Pathology and Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Stenmark-Askmalm
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
mesh_terms: D001665:Binding Sites / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D000089804:Shelterin Complex; D019098:Telomerase / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; C440849:POT1 protein, human; D012333:RNA, Messenger; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C509186:TERT protein, human; D019098:Telomerase
keywords: IDH1 mutation; IL-6; TERT polymorphism; TERT promoter mutations; glioblastoma