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Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis
  1. Christian Mirian1,
  2. Anne Katrine Duun-Henriksen2,
  3. Tareq Juratli3,4,
  4. Felix Sahm5,6,
  5. Sabine Spiegl-Kreinecker7,
  6. Matthieu Peyre8,
  7. Annamaria Biczok5,9,
  8. Jörg-Christian Tonn5,9,
  9. Stéphane Goutagny10,
  10. Luca Bertero11,
  11. Andrea Daniela Maier1,
  12. Maria Møller Pedersen1,
  13. Ian Law12,
  14. Helle Broholm13,
  15. Daniel P. Cahill3,
  16. Priscilla Brastianos14,
  17. Lars Poulsgaard1,
  18. Kåre Fugleholm1,
  19. Morten Ziebell1,
  20. Tina Munch1,15,16,
  21. Tiit Mathiesen1,16,17
  1. 1 Department of Neurosurgery, Copenhagen, Copenhagen University Hospital, Denmark
  2. 2 Danish Cancer Society Research Center, Statistics and Pharmacoepidemiology, Copenhagen, Denmark
  3. 3 Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, United States
  4. 4 Department of Neurosurgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  5. 5 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
  6. 6 Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
  7. 7 Department of Neurosurgery, Kepler University Hospital GmbH, Johannes Kepler University, Linz, Austria
  8. 8 Department of Neurosurgery, Sorbonne Université, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
  9. 9 Department of Neurosurgery, Ludwig-Maximilians-University Munich, Munich, Germany
  10. 10 Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Clichy, Paris, France
  11. 11 Department of Medical Sciences, Pathology Unit, University of Turin, Torino, Italy
  12. 12 Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Copenhagen, Denmark
  13. 13 Department of Neuropathology, Center of Diagnostic Investigation, Copenhagen University Hospital, Copenhagen, Denmark
  14. 14 Department of Medicine, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  15. 15 Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  16. 16 Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  17. 17 Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
  1. Correspondence to Dr Christian Mirian, Department of Neurosurgery, Copenhagen 2100, Denmark; christian.mirian.larsen{at}regionh.dk

Abstract

Background TERT gene alterations (TERT-alt) have been linked to increased risk of recurrence in meningiomas, whereas the association to mortality largely remain incompletely investigated. As incongruence between clinical course and WHO grade exists, reliable biomarkers have been sought.

Methods We applied the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data Statement. We compiled data from eight studies and allocated patients to TERT-alt (n=59) or TERT promoter wild-type (TERTp-wt; n=618). We compared the two groups stratified for WHO grades as: incidence rates, survival probabilities and cumulative recurrences. We estimated the effects of WHO grade, age at diagnosis and sex as HRs.

Results TERT-alt occurred in 4.7%, 7.9% and 15.4% of WHO-I/WHO-II/WHO-III meningiomas, respectively. The median recurrence-free survival was 14 months for all TERT-alt patients versus 101 months for all TERTp-wt patients. The HR for TERT-alt was 3.74 in reference to TERTp-wt. For all TERT-alt patients versus all TERTp-wt patients, the median overall survival was 58 months and 160 months, respectively. The HR for TERT-alt was 2.77 compared with TERTp-wt. TERT-alt affected prognosis independent of WHO grades. Particularly, the recurrence rate was 4.8 times higher in WHO-I/-II TERT-alt patients compared with WHO-III TERTp-wt patients. The mortality rate was 2.7 times higher in the WHO-I and WHO-II TERT-alt patients compared with WHO-III TERTp-wt patients.

Conclusions TERT-alt is an important biomarker for significantly higher risk of recurrence and death in meningiomas. TERT-alt should be managed and surveilled aggressively. We propose that TERT-alt analysis should be implemented as a routine diagnostic test in meningioma and integrated into the WHO classification.

Trial registration number PROSPERO: CRD42018110566.

  • TERT
  • meningioma
  • alteration
  • meta-analysis
  • brain tumors
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Footnotes

  • Contributors Study design, idea and writing: CM (lead writer), ADM, MMP, IL, HB, LP, KF, MZ, TinM and TiiM. Statistics and methods: CM, AKD-H (certified statistician) and TinM (epidemiologist). Producing data and patient follow-up: TJ, FS, SS-K, MP, AB, J-CT, SG, LB, DPC and PB. Editing and formatting the manuscript: all.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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