title: Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes.
abstract: OBJECTIVE
  To identify the prognostic significance of TERT promoter mutations (TERTp-mut) and their associations with common molecular alterations in glioblastomas (GBMs).
  
  
  METHODS
  We sequenced the TERTp-mut in DNA from 395 GBMs and analyzed the results with their respective histology, genetic profile (IDH1 mutation, EGFR amplification, CDKN2A homozygous deletion, loss of chromosome 10, TP53 mutation), and overall survival (OS).
  
  
  RESULTS
  TERTp-mut were found in 299 of 395 GBMs (75.7%) and were associated with an older age (median 59.6 years for TERTp-mut vs 53.6 years for TERT promoter wild type [TERTp-wt], p < 0.0001). TERTp-mut was an independent factor of poor prognosis (OS = 13.8 vs 18.4 months), in both IDH-mutated (OS = 13.8 vs 37.6 months, p = 0.022) and IDH-wt GBMs (OS = 13.7 vs 17.5 months, p = 0.006). TERTp-mut was associated with IDH-wt, EGFR amplification, CDKN2A deletion, and chromosome 10q loss, but not with MGMT promoter methylation. In the TERTp-wt group, OS was twice longer in EGFR-wt than in EGFR amplification GBMs (OS = 26.6 vs 13.3 months; p = 0.005). In the EGFR-wt group, patients with TERTp-wt had a significantly better outcome (OS = 26.3 vs 12.5 months, p < 0.0001), whereas in the EGFR amplification group, patients with TERTp-mut survived longer (OS = 15.8 vs 13.3 months, p = 0.05). Taken together, the absence of both EGFR amplification and TERTp-mut is associated with longer survival in patients with GBM (26.5 months for patients with IDH-wt, 36.7 months for patients with IDH mutation).
  
  
  CONCLUSIONS
  The analysis of TERTp-mut, in combination with EGFR amplification and IDH mutation status, refines the prognostic classification of GBMs.
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Marianne
authors.initials: M
authors.lastname: Labussière
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Blandine
authors.initials: B
authors.lastname: Boisselier
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Karima
authors.initials: K
authors.lastname: Mokhtari
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Anna-Luisa
authors.initials: AL
authors.lastname: Di Stefano
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Anais
authors.initials: A
authors.lastname: Rahimian
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Rossetto
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Ciccarino
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Olivier
authors.initials: O
authors.lastname: Saulnier
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Rosina
authors.initials: R
authors.lastname: Paterra
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marie
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Finocchiaro
authors.affiliation: From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy. marc.sanson@psl.aphp.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015254:DNA Modification Methylases / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D019098:Telomerase / Q000235:genetics*; D055815:Young Adult
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C512478:EGFR protein, human; D066246:ErbB Receptors; C509186:TERT protein, human; D019098:Telomerase