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Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT

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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.

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Acknowledgements

Work at University of California, San Francisco, was supported by the National Institutes of Health (Grant Numbers R01CA52689, P50CA097257, R01CA126831, R01CA139020 and R25CA112355), as well as the loglio Collective, the National Brain Tumor Foundation, The Sontag Foundation, the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research, the Robert Magnin Newman Endowed Chair in Neuro-oncology, and by donations from families and friends of John Berardi, Helen Glaser, Elvera Olsen, Raymond E. Cooper, and William Martinusen.

Work at the Mayo Clinic was supported by the National Institutes of Health (Grant Numbers P50CA108961 and P30CA15083), National Institute of Neurological Disorders and Stroke (Grant Number RC1NS068222Z), the Bernie and Edith Waterman Foundation, and the Ting Tsung and Wei Fong Chao Family Foundation.

This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1RR024131. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Sect. 103885; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement # U58DP003862-01 awarded to the California Department of Public Health. The ideas and opinions expressed herein are those of the author(s) and endorsement by the State of California Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors is not intended nor should be inferred.

The results published here are in whole or part based upon data generated by The Cancer Genome Atlas managed by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov.

The authors wish to acknowledge study participants, the clinicians and research staff at the participating medical centers, the UCSF Helen Diller Family Comprehensive Cancer Center Genome Analysis Core which is supported by a National Cancer Institute Cancer Center Support Grant (5P30CA082103), the UCSF Cancer Registry, the UCSF Neurosurgery Tissue Bank, Katherine Cornelius, the late Dr. Bernd Scheithauer, the Mayo Clinic Center for Individualized Medicine, and the Mayo Clinic Comprehensive Cancer Center Biospecimens and Processing and Genotyping Shared Resources.

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    Authors and Affiliations

    1. Department of Pathology, University of California, Box 0102, 505 Parnassus Avenue, Room M-551, San Francisco, CA, 94143, USA

      Melike Pekmezci & Arie Perry

    2. Department of Anatomic Pathology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA

      Melike Pekmezci

    3. Department of Neurological Surgery, University of California, San Francisco, CA, USA

      Terri Rice, Annette M. Molinaro, Kyle M. Walsh, Helen Hansen, Lucie S. McCoy, Arie Perry, Tarik Tihan, Mitchel S. Berger, Jennifer Clarke, Jennie W. Taylor, John K. Wiencke & Margaret R. Wrensch

    4. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA

      Annette M. Molinaro, Kyle M. Walsh, Joseph L. Wiemels & Paige M. Bracci

    5. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

      Paul A. Decker, Hugues Sicotte & Jeanette E. Eckel-Passow

    6. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

      Thomas M. Kollmeyer, Gobinda Sarkar, Caterina Giannini & Robert B. Jenkins

    7. Department of Neurology, Mayo Clinic, Rochester, MN, USA

      Daniel H. Lachance

    8. Department of Radiology, University of California, San Francisco, CA, USA

      Joseph L. Wiemels & Tracy Luks

    9. Institute of Human Genetics, University of California, San Francisco, CA, USA

      John K. Wiencke & Margaret R. Wrensch

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    1. Melike Pekmezci
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    Correspondence to Melike Pekmezci.

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    All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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    Informed consent was obtained from all individual participants included in this study.

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    R. B. Jenkins and M. R. Wrensch contributed equally to this publication.

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    Supplementary Table 1 Deidentified raw data for all 643 Mayo and UCSF cases (XLSX 42 kb)

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    Pekmezci, M., Rice, T., Molinaro, A.M. et al. Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT . Acta Neuropathol 133, 1001–1016 (2017). https://doi.org/10.1007/s00401-017-1690-1

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