title: Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT.
abstract: The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: (1) Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; (2) Astrocytoma, IDH-mutant; (3) Glioblastoma, IDH-mutant; (4) Glioblastoma, IDH-wildtype; and (5) Astrocytoma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations of overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95% CI 1.05-7.04, p = 0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI 0.17-0.81, p = 0.01). Among Group 5, IDH-wildtype astrocytomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI 0.27-0.87), p = 0.02). Thus, we present evidence that in certain WHO 2016 diagnostic groups, testing for TERT promoter mutations or ATRX alterations may provide additional useful prognostic information.
authors.affiliation: Department of Pathology, University of California, Box 0102, 505 Parnassus Avenue, Room M-551, San Francisco, CA, 94143, USA. melike.pekmezci@ucsf.edu.|Department of Anatomic Pathology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA. melike.pekmezci@ucsf.edu.
authors.forename: Melike
authors.identifier: 0000-0003-2548-8359
authors.initials: M
authors.lastname: Pekmezci
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Terri
authors.initials: T
authors.lastname: Rice
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.|Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.|Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Decker
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Hansen
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Hugues
authors.initials: H
authors.lastname: Sicotte
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kollmeyer
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Lucie S
authors.initials: LS
authors.lastname: McCoy
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Gobinda
authors.initials: G
authors.lastname: Sarkar
authors.affiliation: Department of Pathology, University of California, Box 0102, 505 Parnassus Avenue, Room M-551, San Francisco, CA, 94143, USA.|Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.|Department of Radiology, University of California, San Francisco, CA, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Lachance
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clarke
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Jennie W
authors.initials: JW
authors.lastname: Taylor
authors.affiliation: Department of Radiology, University of California, San Francisco, CA, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Luks
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.|Institute of Human Genetics, University of California, San Francisco, CA, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.|Institute of Human Genetics, University of California, San Francisco, CA, USA.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D011379:Prognosis; D019098:Telomerase / Q000235:genetics*; D014944:World Health Organization; D000075924:X-linked Nuclear Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C509186:TERT protein, human; D019098:Telomerase; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ATRX alteration; Brain tumor prognosis; Glioma classification; TERT promoter mutation; Telomere maintenance