Telomerase reverse transcriptase promoter mutation- and O6-methylguanine DNA methyltransferase promoter methylation-mediated sensitivity to temozolomide in isocitrate dehydrogenase-wild-type glioblastoma: is there a link?

Dorothee Gramatzki; Jörg Felsberg; Bettina Hentschel; Marietta Wolter; Gabriele Schackert; Manfred Westphal; Luca Regli; Niklas Thon; Marcos Tatagiba; Wolfgang Wick; Uwe Schlegel; Dietmar Krex; Jakob Matschke; Patrick Roth; Marian P Suresh; Marcel A Kamp; Elisabeth J Rushing; Torsten Pietsch; Andreas von Deimling; Michael Sabel; Markus Loeffler; Michael Weller; Guido Reifenberger

doi:10.1016/j.ejca.2021.01.014

Telomerase reverse transcriptase promoter mutation- and O⁶-methylguanine DNA methyltransferase promoter methylation-mediated sensitivity to temozolomide in isocitrate dehydrogenase-wild-type glioblastoma: is there a link?

Eur J Cancer. 2021 Apr:147:84-94. doi: 10.1016/j.ejca.2021.01.014. Epub 2021 Feb 22.

Authors

Dorothee Gramatzki¹, Jörg Felsberg², Bettina Hentschel³, Marietta Wolter², Gabriele Schackert⁴, Manfred Westphal⁵, Luca Regli⁶, Niklas Thon⁷, Marcos Tatagiba⁸, Wolfgang Wick⁹, Uwe Schlegel¹⁰, Dietmar Krex⁴, Jakob Matschke¹¹, Patrick Roth¹², Marian P Suresh¹³, Marcel A Kamp¹³, Elisabeth J Rushing¹⁴, Torsten Pietsch¹⁵, Andreas von Deimling¹⁶, Michael Sabel¹³, Markus Loeffler³, Michael Weller¹², Guido Reifenberger¹⁷

Affiliations

¹ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland. Electronic address: [email protected].
² Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany.
³ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁴ Department of Neurosurgery, University of Dresden, Dresden, Germany.
⁵ Department of Neurosurgery, University of Hamburg, Hamburg, Germany.
⁶ Department of Neurosurgery, University Hospital and University of Zurich, Zurich, Switzerland.
⁷ Department of Neurosurgery, Ludwig-Maximilians-University Munich, Munich, Germany.
⁸ Department of Neurosurgery / Interdisciplinary Division of Neuro-Oncology, University of Tübingen, Tübingen, Germany.
⁹ Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neurooncology German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Department of Neurology, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
¹¹ Institute of Neuropathology, University of Hamburg, Hamburg, Germany.
¹² Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
¹³ Department of Neurosurgery, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany.
¹⁴ Department of Neuropathology, University Hospital and University of Zurich, Zurich, Switzerland.
¹⁵ Department of Neuropathology, DGNN Brain Tumor Reference Center, University Hospital Bonn, Bonn, Germany.
¹⁶ Department of Neuropathology, University Hospital Heidelberg, And CCU Neuropathology, and DKTK, German Cancer Center (DKFZ), Heidelberg, Germany.
¹⁷ Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany; German Cancer Consortium, Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: [email protected].

PMID: 33631540
DOI: 10.1016/j.ejca.2021.01.014

Abstract

Aim of the study: Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wild-type glioblastoma is essentially limited to patients with O⁶-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma.

Methods: MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH-wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302).

Results: In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter-unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07-2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter-methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes.

Conclusions: Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH-wild-type glioblastoma.

Keywords: Glioblastoma; IDH–; MGMT; Survival; TERT; Temozolomide; wild-type.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Alkylating / therapeutic use*
Brain Neoplasms / drug therapy*
Brain Neoplasms / enzymology
Brain Neoplasms / genetics
Brain Neoplasms / pathology
DNA Methylation*
DNA Modification Methylases / genetics*
DNA Repair Enzymes / genetics*
Drug Resistance, Neoplasm / genetics
Female
Germany
Humans
Isocitrate Dehydrogenase / genetics*
Male
Middle Aged
Mutation*
Promoter Regions, Genetic*
Retrospective Studies
Switzerland
Telomerase / genetics*
Temozolomide / therapeutic use*
Treatment Outcome
Tumor Suppressor Proteins / genetics*

Substances

Antineoplastic Agents, Alkylating
Tumor Suppressor Proteins
Isocitrate Dehydrogenase
DNA Modification Methylases
MGMT protein, human
TERT protein, human
Telomerase
DNA Repair Enzymes
Temozolomide