title: Prognostic quality of activating TERT promoter mutations in glioblastoma: interaction with the rs2853669 polymorphism and patient age at diagnosis.
abstract: BACKGROUND
  Expression of the telomerase reverse transcriptase (TERT) might be altered by activating mutations of the rs2853669 polymorphism within the promoter region. Here we investigate the impact of these genomic alterations on telomerase activation and dissect their prognostic potential in glioblastoma (GBM).
  
  
  METHODS
  The respective TERT promoter region was sequenced in 126 GBM tissues and compared with clinical parameters and glioma biomarkers MGMT promoter methylation and IDH1 mutation. TERT mRNA expression, telomerase activity, and telomere lengths were determined by reverse transcriptase PCR, TRAP assay, and real-time PCR, respectively.
  
  
  RESULTS
  Seventy-three percent of GBM patients harbored TERT promoter mutations associated with enhanced telomerase activity and TERT mRNA expression but reduced telomere lengths (P < .001 for all). Patients with mutated tumors exhibited significantly shorter overall survival in the entire cohort (11.5 vs 23.1 months; P < .0001) and in the primary GBM patient subgroup lacking IDH1 mutations (n = 120; P = .0084). This prognostic impact was confined to younger patients (aged <65 years), while the negative prognostic power of enhanced age at diagnosis was limited to those patients lacking TERT promoter mutations. Presence of the common single nucleotide polymorphism rs2853669, disrupting an endogenous Ets2 transcription factor-binding site, was associated with improved survival exclusively in patients with a wild-type TERT promoter. On the contrary, the shortest mean overall survival was detected in those patients harboring both an activating TERT promoter mutation and homozygous rs2853669 alleles.
  
  
  CONCLUSIONS
  In summary, TERT promoter mutations are powerful prognosticators for worse course of disease in human GBM patients but their prognostic value is influenced by the rs2853669 polymorphism and age at diagnosis.
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Sabine
authors: S
authors: Spiegl-Kreinecker
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Daniela
authors: D
authors: Lötsch
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Bahil
authors: B
authors: Ghanim
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Christine
authors: C
authors: Pirker
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Thomas
authors: T
authors: Mohr
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Magdalena
authors: M
authors: Laaber
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Serge
authors: S
authors: Weis
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Alfred
authors: A
authors: Olschowski
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Gerald
authors: G
authors: Webersinke
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Josef
authors: J
authors: Pichler
authors: Department of Neurosurgery, Wagner-Jauregg Hospital, Linz, Austria (S.S.-K., M.L., A.O.); Institute of Pathology and Neuropathology, Wagner-Jauregg Hospital, Linz, Austria (S.W.); Department of Internal Medicine, Wagner-Jauregg Hospital, Linz, Austria (J.P.); Institute of Cancer Research and Comprehensive Cancer Center-Central Nervous System Tumors Unit, Department of Medicine I, Medical University of Vienna, Vienna, Austria (D.L., C.P., T.M., W.B.); Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria (B.G.); Laboratory of Molecular Biology and Tumorcytogenetics, Hospital Barmherzige Schwestern, Linz, Austria (G.W.).
authors: Walter
authors: W
authors: Berger
mesh_terms: D000367:Age Factors; D000368:Aged; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C509186:TERT protein, human; D019098:Telomerase
keywords: glioblastoma; prognostic marker; rs2853669, TERT promoter mutations; telomerase