title: TERT promoter mutations and rs2853669 polymorphism: prognostic impact and interactions with common alterations in glioblastomas.
abstract: TERT promoter (TERTp) mutation is the most common mutation in glioblastomas. It creates a putative binding site for Ets/TCF transcription factors, enhancing telomerase expression and activity, whereas the rs2853669 variant disrupts another Ets/TCF binding. We explore here the interaction between these two alterations, tumor genomic profile and the impact on prognosis. The TERTp and rs2853669 statuses were determined and confronted with the outcome and molecular profile, i.e., loss of chromosome 10q, CDKN2A deletion, IDH mutation, EGFR amplification, MGMT promoter methylation. 651 glioblastomas were selected (sex ratio = 1.35, median age 60.4 years, median survival 13.5 months). The TERTp mutation found in 481 patients (74 %) was independent from rs2853669 genotypes. TERTp mutation, but not rs2853669 status, was associated with older age (61.4 vs. 52.8 years). rs2853669 status had no impact on overall survival (OS) either in mutated TERTp or wild-type TERTp. Neither rs2736100 (TERT, 5q15.33) nor rs192011116 (TERC, 3q26.2) status had any impact on survival or showed any association with a TERTp mutation. The TERTp mutation was associated with EGFR amplification chromosome 10q loss, CDKN2A deletion and IDH wt. EGFR amplification was associated with a better outcome in TERTp mutated GBM, and a worse outcome in TERTp WT. This study-the largest analyzing the TERTp mutation and the rs2853669 polymorphism-fails to find any prognostic impact of rs2853669. It confirms the dual prognostic impact of EGFR amplification depending on TERTp status.
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.
authors.forename: Umberto
authors.initials: U
authors.lastname: Nencha
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.|OncoNeuroTek, 75013, Paris, France.
authors.forename: Amithys
authors.initials: A
authors.lastname: Rahimian
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Giry
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sechi
authors.affiliation: Laboratoire de neuropathologie R Escourolle, GH Pitié-Salpêtrière, 75013, Paris, France.
authors.forename: Karima
authors.initials: K
authors.lastname: Mokhtari
authors.affiliation: Laboratoire d'anatomie pathologique, Hôpital Lariboisière, 75010, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Polivka
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Schmitt
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.|AP-HP, GH Pitié-Salpêtrière, Service de Neurologie 2, 75013, Paris, France.
authors.forename: Anna-Luisa
authors.initials: AL
authors.lastname: Di Stefano
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.|AP-HP, GH Pitié-Salpêtrière, Service de Neurologie 2, 75013, Paris, France.
authors.forename: Agusti
authors.initials: A
authors.lastname: Alentorn
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Labussière
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France. marc.sanson@psl.aphp.fr.|AP-HP, GH Pitié-Salpêtrière, Service de Neurologie 2, 75013, Paris, France. marc.sanson@psl.aphp.fr.|Service de Neurologie 2, Groupe Hospitalier Pitié-Salpêtrière, 75651, Paris cedex 13, France. 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; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; 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; C509186:TERT protein, human; D019098:Telomerase
keywords: EGFR; Glioblastoma; Polymorphism; TERT; rs2853669