Review Article | Published:

MGMT testing—the challenges for biomarker-based glioma treatment

Nature Reviews Neurology volume 10, pages 372385 (2014) | Download Citation

Abstract

Many patients with malignant gliomas do not respond to alkylating agent chemotherapy. Alkylator resistance of glioma cells is mainly mediated by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in glioma cells compromises this DNA repair mechanism and increases chemosensitivity. MGMT promoter methylation is, therefore, a strong prognostic biomarker in paediatric and adult patients with glioblastoma treated with temozolomide. Notably, elderly patients (>65–70 years) with glioblastoma whose tumours lack MGMT promoter methylation derive minimal benefit from such chemotherapy. Thus, MGMT promoter methylation status has become a frequently requested laboratory test in neuro-oncology. This Review presents current data on the prognostic and predictive relevance of MGMT testing, discusses clinical trials that have used MGMT status to select participants, evaluates known issues concerning the molecular testing procedure, and addresses the necessity for molecular-context-dependent interpretation of MGMT test results. Whether MGMT promoter methylation testing should be offered to all individuals with glioblastoma, or only to elderly patients and those in clinical trials, is also discussed. Justifications for withholding alkylating agent chemotherapy in patients with MGMT-unmethylated glioblastomas outside clinical trials, and the potential role for MGMT testing in other gliomas, are also discussed.

Key points

  • O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation predicts responsiveness to alkylating chemotherapies in glioblastoma, but is not a prognostic biomarker in gliomas lacking isocitrate dehydrogenase gene mutations

  • Treatment decisions in elderly patients with glioblastoma should take MGMT promoter methylation status into account

  • MGMT testing to select patients with glioblastoma for clinical trials is feasible, and withholding temozolomide from patients without MGMT promoter methylation is justified in this context

  • MGMT-mediated resistance to alkylating chemotherapy is not overcome by alternative dosing schedules, but might be circumvented by the use of alternative treatments

  • Epigenetic inactivation of MGMT might facilitate the induction of point mutations in TP53 and other oncogenes during tumorigenesis and tumour progression

  • Quality-assured MGMT testing should be implemented as a molecular diagnostic method in the next WHO classification of brain tumours

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References

  1. 1.

    , & Adult glioma incidence trends in the United States, 1977–2000. Cancer 101, 2293–2299 (2004).

  2. 2.

    & Malignant gliomas in adults. N. Engl. J. Med. 359, 492–507 (2008).

  3. 3.

    et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).

  4. 4.

    et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J. Clin. Oncol. 27, 5743–5750 (2009).

  5. 5.

    et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 27, 4733–4740 (2009).

  6. 6.

    et al. Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014).

  7. 7.

    et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014).

  8. 8.

    et al. Survival and quality of life in the randomized, multicenter GLARIUS trial investigating bevacizumab/irinotecan versus standard temozolomide in newly diagnosed, MGMT-non-methylated glioblastoma patients. J. Clin. Oncol. 32 (Suppl. 5), 2042 (2014).

  9. 9.

    et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter: key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study. J. Clin. Oncol. 31 (Suppl. 3), 2009 (2013).

  10. 10.

    et al. A randomized phase II study investigating cilengitide added to standard chemoradiotherapy in patients with newly diagnosed glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter: initial report of the CORE study. Eur. J. Cancer 49 (Suppl. 3), S17–S18 (2013).

  11. 11.

    et al. Enzastaurin before and concomitant with radiation therapy, followed by enzastaurin maintenance therapy, in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation. Neuro. Oncol. 15, 1405–1412 (2013).

  12. 12.

    et al. Radiation therapy and concurrent plus adjuvant temsirolimus (CCI-779) versus chemo-irradiation with temozolomide in newly diagnosed glioblastoma without methylation of the MGMT gene promoter. J. Clin. Oncol. 32 (Suppl. 5), 2003 (2014).

  13. 13.

    et al. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br. J. Cancer 88, 1004–1011 (2003).

  14. 14.

    et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J. Clin. Oncol. 31, 4085–4091 (2013).

  15. 15.

    et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 13, 707–715 (2012).

  16. 16.

    et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 13, 916–926 (2012).

  17. 17.

    et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J. Clin. Oncol. 27, 740–745 (2009).

  18. 18.

    et al. Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J. Clin. Oncol. 25, 3357–3361 (2007).

  19. 19.

    et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J. Clin. Oncol. 28, 2051–2057 (2010).

  20. 20.

    et al. Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Br. J. Cancer 95, 1155–1160 (2006).

  21. 21.

    et al. Phase 2 study of dose-intense temozolomide in recurrent glioblastoma. Neuro. Oncol. 15, 930–935 (2013).

  22. 22.

    et al. Phase II study of protracted daily temozolomide for low-grade gliomas in adults. Clin. Cancer Res. 15, 330–337 (2009).

  23. 23.

    et al. Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int. J. Cancer 129, 659–670 (2011).

  24. 24.

    et al. Intracellular localization and intercellular heterogeneity of the human DNA repair protein O6-methylguanine-DNA methyltransferase. Cancer Chemother. Pharmacol. 37, 547–555 (1996).

  25. 25.

    & Self-destruction and tolerance in resistance of mammalian cells to alkylation damage. Nucleic Acids Res. 20, 2933–2940 (1992).

  26. 26.

    & Genomic instability and tolerance to alkylating agents. Cancer Surv. 28, 69–85 (1996).

  27. 27.

    & Targeted modulation of MGMT: clinical implications. Clin. Cancer Res. 12, 328–331 (2006).

  28. 28.

    & O6-benzylguanine and its role in chemotherapy. Clin. Cancer Res. 3, 837–47 (1997).

  29. 29.

    et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med. 343, 1350–1354 (2000).

  30. 30.

    et al. Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma. J. Clin. Oncol. 16, 3570–3575 (1998).

  31. 31.

    , & Depletion of mammalian O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents. Proc. Natl Acad. Sci. USA 87, 5368–5372 (1990).

  32. 32.

    et al. Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene. Mol. Cell Biol. 17, 5612–5619 (1997).

  33. 33.

    et al. Silencing effect of CpG island hypermethylation and histone modifications on O6-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer. Oncogene 22, 8835–8844 (2003).

  34. 34.

    et al. Optimization of quantitative MGMT promoter methylation analysis using pyrosequencing and combined bisulfite restriction analysis. J. Mol. Diagn. 9, 368–381 (2007).

  35. 35.

    et al. Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas. Neuro. Oncol. 11, 348–356 (2009).

  36. 36.

    et al. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat. Rev. Neurol. 6, 39–51 (2010).

  37. 37.

    et al. Extent and patterns of MGMT promoter methylation in glioblastoma- and respective glioblastoma-derived spheres. Clin. Cancer Res., 17, 255–266 (2011).

  38. 38.

    et al. The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide. Mol. Cancer Ther. 13, 1334–1344 (2014).

  39. 39.

    et al. The essential role of histone H3 Lys9 di-methylation and MeCP2 binding in MGMT silencing with poor DNA methylation of the promoter CpG island. J. Biochem. 137, 431–440 (2005).

  40. 40.

    et al. Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts. Clin. Cancer Res. 18, 4070–4079 (2012).

  41. 41.

    , & Methylation-related chromatin structure is associated with exclusion of transcription factors from and suppressed expression of the O-6-methylguanine DNA methyltransferase gene in human glioma cell lines. Mol. Cell Biol. 14, 6515–6521 (1994).

  42. 42.

    et al. Novel mechanism whereby nuclear factor κB mediates DNA damage repair through regulation of O6-methylguanine-DNA-methyltransferase. Cancer Res. 67, 8952–8959 (2007).

  43. 43.

    & Regulation of the human O6-methylguanine-DNA methyltransferase gene by transcriptional coactivators cAMP response element-binding protein-binding protein and p300. J. Biol. Chem. 275, 34197–34204 (2000).

  44. 44.

    et al. Regulation of expression of the DNA repair gene O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling. Cancer Res. 58, 3950–3956 (1998).

  45. 45.

    , , & Wild-type p53 suppresses transcription of the human O6-methylguanine-DNA methyltransferase gene. Cancer Res. 56, 2029–2032 (1996).

  46. 46.

    et al. Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem Cells 28, 851–862 (2010).

  47. 47.

    et al. BMP2 sensitizes glioblastoma stem-like cells to temozolomide by affecting HIF-1α stability and MGMT expression. Cell Death Dis. 3, e412 (2012).

  48. 48.

    et al. mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy. Proc. Natl Acad. Sci. USA 111, 409–414 (2014).

  49. 49.

    et al. In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing. Acta Neuropathol. 125, 671–681 (2013).

  50. 50.

    , , & miR-181b modulates glioma cell sensitivity to temozolomide by targeting MEK1. Cancer Chemother. Pharmacol. 72, 147–158 (2013).

  51. 51.

    et al. miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression. Neuro Oncol. 14, 712–719 (2012).

  52. 52.

    et al. miR-221/222 target the DNA methyltransferase MGMT in glioma cells. PLoS ONE 8, e74466 (2013).

  53. 53.

    et al. DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J. Clin. Oncol. 16, 3851–3857 (1998).

  54. 54.

    et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin. Cancer Res. 10, 1871–1874 (2004).

  55. 55.

    et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).

  56. 56.

    et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).

  57. 57.

    et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).

  58. 58.

    et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).

  59. 59.

    & Mutator pathways unleashed by epigenetic silencing in human cancer. Mutagenesis 22, 247–253 (2007).

  60. 60.

    et al. Both base excision repair and O6-methylguanine-DNA methyltransferase protect against methylation-induced colon carcinogenesis. Carcinogenesis 31, 2111–2117 (2010).

  61. 61.

    et al. DNA repair gene O6-methylguanine-DNA methyltransferase: promoter hypermethylation associated with decreased expression and G:C to A:T mutations of p53 in brain tumors. Mol. Carcinog. 36, 23–31 (2003).

  62. 62.

    et al. Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C A:T mutations of the TP53 tumor suppressor gene. Carcinogenesis 22, 1715–1719 (2001).

  63. 63.

    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  64. 64.

    et al. Intratumoral homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas. Int. J. Cancer 121, 2458–2464 (2007).

  65. 65.

    et al. Temozolomide-mediated DNA methylation in human myeloid precursor cells: differential involvement of intrinsic and extrinsic apoptotic pathways. Clin. Cancer Res. 19, 2699–2709 (2013).

  66. 66.

    et al. Tumor-associated mutations in O6-methylguanine DNA-methyltransferase (MGMT) reduce DNA repair functionality. Mol. Carcinog. 53, 201–210 (2014).

  67. 67.

    , , & DNA methylation biomarkers in cancer: progress towards clinical implementation. Expert Rev. Mol. Diagn. 12, 473–487 (2012).

  68. 68.

    et al. Predominant influence of MGMT methylation in non-resectable glioblastoma after radiotherapy plus temozolomide. J. Neurol. Neurosurg. Psychiatry 82, 441–446 (2011).

  69. 69.

    Prevention of PCR cross-contamination by UNG treatment of bisulfite-treated DNA. Methods Mol. Biol. 507, 357–370 (2009).

  70. 70.

    et al. Relationship between expression of O6-methylguanine-DNA methyltransferase, glutathione-S-transferase π in glioblastoma and the survival of the patients treated with nimustine hydrochloride: an immunohistochemical analysis. Neurol. Res. 25, 241–248 (2003).

  71. 71.

    et al. Prognostic value of three different methods of MGMT promoter methylation analysis in a prospective trial on newly diagnosed glioblastoma. PLoS ONE 7, e33449 (2012).

  72. 72.

    et al. MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta Neuropathol. 124, 547–560 (2012).

  73. 73.

    , , & Pitfalls in the assessment of MGMT expression and in its correlation with survival in diffuse astrocytomas: proposal of a feasible immunohistochemical approach. Acta Neuropathol. 115, 249–259 (2008).

  74. 74.

    et al. O6-methylguanine-DNA methyltransferase activity in breast and brain tumors. Int. J. Cancer 61, 321–326 (1995).

  75. 75.

    et al. O6-methylguanine-DNA methyltransferase (MGMT) mRNA expression predicts outcome in malignant glioma independent of MGMT promoter methylation. PLoS ONE 6, e17156 (2011).

  76. 76.

    et al. Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma. J. Mol. Diagn. 10, 332–337 (2008).

  77. 77.

    et al. European Consensus Conference for external quality assessment in molecular pathology. Ann. Oncol. 24, 1958–1963 (2012).

  78. 78.

    et al. Improvement in the quality of molecular analysis of EGFR in non-small-cell lung cancer detected by three rounds of external quality assessment. J. Clin. Pathol. 66, 319–325 (2013).

  79. 79.

    et al. External quality assessment of BRAF molecular analysis in melanoma. J. Clin. Pathol. 67, 120–124 (2014).

  80. 80.

    et al. Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group. BMC Cancer 13, 472 (2013).

  81. 81.

    et al. Interlaboratory comparison of IDH mutation detection. J. Neurooncol. 112, 173–178 (2013).

  82. 82.

    et al. Molecular diagnostics of glioma—results of the first interlaboratory comparison of MGMT promoter methylation testing at twenty-three academic centers in Germany, Austria and the Netherlands. Clin. Neuropathol. 32, 414–415 (2013).

  83. 83.

    et al. EANO guideline on the diagnosis and treatment of malignant glioma. Lancet Oncol. (in press).

  84. 84.

    et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC–NCIC trial. Lancet Oncol. 10, 459–466 (2009).

  85. 85.

    et al. Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial. J. Clin. Oncol. 29, 3050–3055 (2011).

  86. 86.

    et al. Predictive impact of MGMT promoter methylation in glioblastoma of the elderly. Int. J. Cancer 131, 1342–1350 (2012).

  87. 87.

    et al. Malignant astrocytomas of elderly patients lack favorable molecular markers: an analysis of the NOA-08 study collective. Neuro Oncol. 15, 1017–1026 (2013).

  88. 88.

    & Isocitrate dehydrogenase mutations: a challenge to traditional views on the genesis and malignant progression of gliomas. Glia 59, 1200–1204 (2011).

  89. 89.

    et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J. Clin. Oncol. 27, 5874–5880 (2009).

  90. 90.

    et al. MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. J. Clin. Oncol. 27, 5881–5886 (2009).

  91. 91.

    et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).

  92. 92.

    et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012).

  93. 93.

    et al. Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology 81, 1515–1522 (2013).

  94. 94.

    et al. MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic oligodendrogliomas and oligoastrocytomas. A report from EORTC study 26951. Clin. Cancer Res. 19, 5513–5522 (2013).

  95. 95.

    et al. Reporting recommendations for tumor marker prognostic studies. J. Clin. Oncol. 23, 9067–9072 (2005).

  96. 96.

    Assessing and comparing the performance of molecular diagnostic tests. J. Mol. Diagn. 16, 1–2 (2014).

  97. 97.

    et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).

  98. 98.

    et al. Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03. J. Clin. Oncol. 24, 4412–4417 (2006).

  99. 99.

    et al. Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. J. Clin. Oncol. 27, 1257–1261 (2009).

  100. 100.

    et al. Toxicity from chemoradiotherapy in older patients with glioblastoma multiforme. J. Neurooncol. 89, 97–103 (2008).

  101. 101.

    et al. MGMT methylation is a prognostic biomarker in elderly patients with newly diagnosed glioblastoma. Neurology 73, 1509–1510 (2009).

  102. 102.

    et al. A prospective study on glioblastoma in the elderly. Cancer 97, 657–662 (2003).

  103. 103.

    et al. Phase II study of short-course radiotherapy plus concomitant and adjuvant temozolomide in elderly patients with glioblastoma. Int. J. Radiat. Oncol. Biol. Phys. 83, 93–99 (2012).

  104. 104.

    , , , & Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl Acad. Sci. USA 93, 9821–9826 (1996).

  105. 105.

    , & A sequencing method based on real-time pyrophosphate. Science 281, 363–365 (1998).

  106. 106.

    Bisulfite sequencing. Wikipedia , (2014).

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Acknowledgements

The authors thank David Capper and Benedikt Wiestler for useful discussions and the provision of data obtained from searches of The Cancer Genome Atlas database.

Author information

Affiliations

  1. German Cancer Consortium, Clinical Cooperation Units Neuro-oncology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

    • Wolfgang Wick
    •  & Markus Weiler
  2. Neuropathology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

    • Andreas von Deimling
  3. Division of Epigenetics and Risk Factors, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

    • Christoph Plass
  4. Neuroimmunology and Brain Tumour Immunology, German Cancer Research Centre, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

    • Michael Platten
  5. Department of Neurology, University Hospital Zurich, Switzerland.

    • Michael Weller
  6. Department of Neurology/Neuro-oncology, Erasmus MC Cancer Institute, Netherlands.

    • Martin van den Bent
  7. Service de Neurologie 2, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, France.

    • Marc Sanson
  8. Department of Clinical Neurosciences, University Hospital Lausanne, Switzerland.

    • Monika Hegi
  9. Department of Neuropathology, Heinrich Heine University, Germany.

    • Guido Reifenberger

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Contributions

W.W., M.v.d.B., M. Weiler, C.P., M.H., M.P and G.R. researched data for the article. W.W., M. Weller, M.S., M. Weiler, A.v.D., C.P., M.H. and G.R. made substantial contributions to the discussion of content. W.W., M. Weller, M.v.d.B., M.H., M.P. and G.R. contributed equally to writing the article. All authors contributed to the review and editing of the manuscript before submission.

Competing interests

W.W. has received consulting and lecture fees from MagForce, Merck Sharp & Dohme, and Roche, and research support from Apogenix, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme and Roche. He also serves on the Steering Committees of the AVAglio and CENTRIC trials, and is lead investigator of other trials in glioma. M. Weller has received research grants from Isarna Therapeutics, Bayer, Merck Serono, Merck Sharp & Dohme and Roche, and honoraria for lectures or advisory boards from Isarna Therapeutics, MagForce, Merck Serono, Merck Sharp & Dohme and Roche. M.v.d.B. acts as a consultant and is a member of the speakers' bureau for Merck Sharp & Dohme. M.S. has received honoraria from Merck Serono. M.H. has acted as a consultant for MDx Health, Merck Serono, Merck Sharp & Dohme and Roche. M.P. has received consultancy and lecture fees from Medac, Merck Serono, and Novartis, and research support from Merck Serono and Novartis. G.R. has received a research grant from Roche, and honoraria from Merck Serono and Roche. The other authors declare no competing interests.

Corresponding author

Correspondence to Wolfgang Wick.

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https://doi.org/10.1038/nrneurol.2014.100

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