title: TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations.
abstract: BACKGROUND
  The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter.
  
  
  METHODS
  We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype.
  
  
  RESULTS
  TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation.
  
  
  CONCLUSIONS
  In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France.
authors.forename: M
authors.initials: M
authors.lastname: Labussière
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] National Neurological Institute C. Mondino, University of Pavia, 27100 Pavia, Italy.
authors.forename: A L
authors.initials: AL
authors.lastname: Di Stefano
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France.
authors.forename: V
authors.initials: V
authors.lastname: Gleize
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] Institut du Cerveau et de la Moelle épinière (ICM), Plateforme de Génotypage Séquençage, Paris 75013, France.
authors.forename: B
authors.initials: B
authors.lastname: Boisselier
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France.
authors.forename: M
authors.initials: M
authors.lastname: Giry
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France.
authors.forename: S
authors.initials: S
authors.lastname: Mangesius
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France.
authors.forename: A
authors.initials: A
authors.lastname: Bruno
authors.affiliation: Dipartimento di Neuro Oncologia Molecolare Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Milano 20134, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Paterra
authors.affiliation: 1] Institut du Cerveau et de la Moelle épinière (ICM), Plateforme de Génotypage Séquençage, Paris 75013, France [2] Onconeurothèque, Paris 75013, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Marie
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] Onconeurothèque, Paris 75013, France.
authors.forename: A
authors.initials: A
authors.lastname: Rahimian
authors.affiliation: Dipartimento di Neuro Oncologia Molecolare Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Milano 20134, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Finocchiaro
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: R S
authors.initials: RS
authors.lastname: Houlston
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris 75013, France.
authors.forename: K
authors.initials: K
authors.lastname: Hoang-Xuan
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris 75013, France.
authors.forename: A
authors.initials: A
authors.lastname: Idbaih
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] Onconeurothèque, Paris 75013, France [5] AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris 75013, France.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Delattre
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] Onconeurothèque, Paris 75013, France [5] AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Laboratoire de Neuropathologie R. Escourolle, Paris 75013, France.
authors.forename: K
authors.initials: K
authors.lastname: Mokhtari
authors.affiliation: 1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] Onconeurothèque, Paris 75013, France [5] AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris 75013, France.
authors.forename: M
authors.initials: M
authors.lastname: Sanson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015996:Survival Rate; D019098:Telomerase / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D007521:Isocitrate Dehydrogenase; C509186:TERT protein, human; D019098:Telomerase