title: TERT promoter mutations: a novel independent prognostic factor in primary glioblastomas.
abstract: BACKGROUND
  Activating somatic mutations in the promoter region of the telomerase reverse transcriptase gene (TERT) have been detected in several cancers. In this study we investigated the TERT promoter mutations and their impact on patient survival in World Health Organization grade IV glioblastoma multiforme (GBM).
  
  
  METHODS
  The TERT core promoter region containing the previously described mutations and a common functional polymorphism (rs2853669) was sequenced in tumors and blood samples from 192 GBM patients. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was assessed by pyrosequencing in 177 (92.2%) cases. Relevant clinical data were obtained from a prospectively maintained electronic database.
  
  
  RESULTS
  We detected specific (-124 C>T and -146 C>T) TERT promoter mutations in 143/178 (80.3%) primary GBM and 4/14 (28.6%) secondary GBM (P < .001). The presence of TERT mutations was associated with poor overall survival, and the effect was confined to the patients who did not carry the variant G-allele for the rs2853669 polymorphism. An exploratory analysis suggested that TERT mutations might be prognostic only in patients who had incomplete resections and no temozolomide chemotherapy.
  
  
  CONCLUSIONS
  In this study, specific TERT promoter mutations were markers of primary GBM and predicted patient survival in conjunction with a common functional polymorphism. The prognostic impact of TERT mutations was absent in patients with complete resections and temozolomide chemotherapy. If confirmed in additional studies, these findings may have clinical implications, that is, TERT mutations appear to characterize tumors that require aggressive treatment.
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany (M.S., K.G., J.S.); German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany (I.H., S.R., B.H., K.H., R.K.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (M.G., A.W.); Center for Primary Health Care Research, Lund University, Malmö, Sweden (K.H.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany (M.S., K.G., J.S.); German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany (I.H., S.R., B.H., K.H., R.K.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (M.G., A.W.); Center for Primary Health Care Research, Lund University, Malmö, Sweden (K.H.).
authors.forename: Ismail
authors.initials: I
authors.lastname: Hosen
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany (M.S., K.G., J.S.); German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany (I.H., S.R., B.H., K.H., R.K.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (M.G., A.W.); Center for Primary Health Care Research, Lund University, Malmö, Sweden (K.H.).
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Gousias
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany (M.S., K.G., J.S.); German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany (I.H., S.R., B.H., K.H., R.K.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (M.G., A.W.); Center for Primary Health Care Research, Lund University, Malmö, Sweden (K.H.).
authors.forename: Sivaramakrishna
authors.initials: S
authors.lastname: Rachakonda
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany (M.S., K.G., J.S.); German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany (I.H., S.R., B.H., K.H., R.K.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (M.G., A.W.); Center for Primary Health Care Research, Lund University, Malmö, Sweden (K.H.).
authors.forename: Barbara
authors.initials: B
authors.lastname: Heidenreich
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany (M.S., K.G., J.S.); German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany (I.H., S.R., B.H., K.H., R.K.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (M.G., A.W.); Center for Primary Health Care Research, Lund University, Malmö, Sweden (K.H.).
authors.forename: Marco
authors.initials: M
authors.lastname: Gessi
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany (M.S., K.G., J.S.); German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany (I.H., S.R., B.H., K.H., R.K.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (M.G., A.W.); Center for Primary Health Care Research, Lund University, Malmö, Sweden (K.H.).
authors.forename: Johannes
authors.initials: J
authors.lastname: Schramm
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany (M.S., K.G., J.S.); German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany (I.H., S.R., B.H., K.H., R.K.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (M.G., A.W.); Center for Primary Health Care Research, Lund University, Malmö, Sweden (K.H.).
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany (M.S., K.G., J.S.); German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany (I.H., S.R., B.H., K.H., R.K.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (M.G., A.W.); Center for Primary Health Care Research, Lund University, Malmö, Sweden (K.H.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Waha
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany (M.S., K.G., J.S.); German Cancer Research Center, Division of Molecular Genetic Epidemiology, Heidelberg, Germany (I.H., S.R., B.H., K.H., R.K.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (M.G., A.W.); Center for Primary Health Care Research, Lund University, Malmö, Sweden (K.H.).
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D005260:Female; D005838:Genotype; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C509186:TERT protein, human; D019098:Telomerase; D045643:DNA Repair Enzymes
keywords: MGMT; TERT mutation; primary glioblastoma multiforme; prognostic factor