Acta Neuropathologica

, Volume 120, Issue 5, pp 585–592 | Cite as

Molecular diagnostics of gliomas: the clinical perspective

  • Ghazaleh TabatabaiEmail author
  • Roger Stupp
  • Martin J. van den Bent
  • Monika E. Hegi
  • Jörg C. Tonn
  • Wolfgang Wick
  • Michael Weller


Significant progress has been made in the molecular diagnostic subtyping of brain tumors, in particular gliomas. In contrast to the classical molecular markers in this field, p53 and epidermal growth factor receptor (EGFR) status, the clinical significance of which has remained controversial, at least three important molecular markers with clinical implications have now been identified: 1p/19q codeletion, O 6-methylguanine methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase-1 (IDH1) mutations. All three are favorable prognostic markers. 1p/19q codeletion and IDH1 mutations are also useful to support and extend the histological classification of gliomas since they are strongly linked to oligodendroglial morphology and grade II/III gliomas, as opposed to glioblastoma, respectively. MGMT promoter methylation is the only potentially predictive marker, at least for alkylating agent chemotherapy in glioblastoma. Beyond these classical markers, the increasing repertoire of anti-angiogenic agents that are currently explored within registration trials for gliomas urgently calls for efforts to identify molecular markers that predict the benefit derived from these novel treatments, too.


Clinical neurooncology Molecular diagnostic Prognostic factor Malignant gliomas Clinical trials 


  1. 1.
    Batchelor TT, Sorensen AG, di Tomaso E et al (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95CrossRefPubMedGoogle Scholar
  2. 2.
    Brandes AA, Franceschi E, Tosoni A, Hegi ME, Stupp R (2008) Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res 14:957–960CrossRefPubMedGoogle Scholar
  3. 3.
    Butowski N, Chang SM, Lamborn KR et al (2010) Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: a phase I study. Neuro-Oncology 12:608–613CrossRefPubMedGoogle Scholar
  4. 4.
    Cairncross G, Berkey B, Shaw E et al (2006) Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 24:2707–2714CrossRefPubMedGoogle Scholar
  5. 5.
    Capper D, Weissert S, Balss J et al (2009) Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol 118:599–601CrossRefPubMedGoogle Scholar
  6. 6.
    Dubbink HJ, Taal W, van Marion R et al (2009) IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology 73:1792–1795CrossRefPubMedGoogle Scholar
  7. 7.
    Friedman H, Prados M, Wen P et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740CrossRefPubMedGoogle Scholar
  8. 8.
    Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and response to temozolomide in glioblastoma. N Engl J Med 352:997–1003CrossRefPubMedGoogle Scholar
  9. 9.
    Issa JP (2004) CpG island methylator phenotype in cancer. Nat Rev Cancer 4:988–993CrossRefPubMedGoogle Scholar
  10. 10.
    Kaloshi G, Benouaich-Amiel A, Diakite F et al (2007) Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome. Neurology 68:1831–1836CrossRefPubMedGoogle Scholar
  11. 11.
    Keime-Guibert F, Chinot O, Taillandier L et al (2007) Radiotherapy for glioblastoma in the elderly. N Engl J Med 356:1527–1535CrossRefPubMedGoogle Scholar
  12. 12.
    Kreisl TN, Kim L, Moore K et al (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745CrossRefPubMedGoogle Scholar
  13. 13.
    Kreisl TN, Kotliarova S, Butman JA et al (2010) A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Neuro-Oncology 12:181–189PubMedGoogle Scholar
  14. 14.
    Lai A, Filka E, McGibbon B et al (2008) Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. Int J Radiat Oncol Biol Phys 71:1372–1380PubMedGoogle Scholar
  15. 15.
    Malmstrom A, Grønberg BH, Stupp R et al. (2010) Glioblastoma (GBM) in elderly patients: a randomized phase III trial comparing survival in patients treated with 6-week radiotherapy (RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemotherapy (TMZ). J Clin Oncol 28:7s (suppl; abstr. LBA2002)Google Scholar
  16. 16.
    Noushmehr H, Weisenberger DJ, Diefes K et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522CrossRefPubMedGoogle Scholar
  17. 17.
    Pignatti F, Van den Bent M, Curran D et al (2002) Prognostic factors for survival in adult patients with cerebral low grade glioma. J Clin Oncol 20:2076–2084CrossRefPubMedGoogle Scholar
  18. 18.
    Reardon DA, Fink KL, Mikkelsen T et al (2008) Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 26:5610–5617CrossRefPubMedGoogle Scholar
  19. 19.
    Ricard D, Kaloshi G, Amiel-Benouaich A et al (2007) Dynamic history of low-grade gliomas before and after temozolomide treatment. Ann Neurol 61:484–490CrossRefPubMedGoogle Scholar
  20. 20.
    Roa W, Brasher PM, Bauman G et al (2004) Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 22:1583–1588CrossRefPubMedGoogle Scholar
  21. 21.
    Sanson M, Marie Y, Paris S et al (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:4150–4154CrossRefPubMedGoogle Scholar
  22. 22.
    Schnell O, Krebs B, Carlsen J et al (2009) Imaging of integrin alpha(v)beta(3) expression in patients with malignant glioma by [18F] Galacto-RGD positron emission tomography. Neuro Oncol 11:861–870CrossRefPubMedGoogle Scholar
  23. 23.
    Scott JN, Brasher PM, Sevick RJ, Rewcastle NB, Forsyth PA (2002) How often are nonenhancing supratentorial gliomas malignant? A population study. Neurology 59:947–949PubMedGoogle Scholar
  24. 24.
    Soffietti R, Baumert B, Bello L et al (2010) Guidelines on management of low-grade gliomas: report of an EFNS-EANO* task force. Eur J Neurol (in press)Google Scholar
  25. 25.
    Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for patients with newly diagnosed glioblastoma. N Engl J Med 352:987–996CrossRefPubMedGoogle Scholar
  26. 26.
    Stupp R, Hegi ME, Mason WP et al (2009) 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 10:459–466CrossRefPubMedGoogle Scholar
  27. 27.
    Stupp R, Hegi ME, Neyns B et al (2010) Phase I//IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 28:2712–2718CrossRefPubMedGoogle Scholar
  28. 28.
    Van den Bent MJ, Carpentier AF, Brandes AA et al (2006) Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol 24:2715–2722CrossRefPubMedGoogle Scholar
  29. 29.
    Van den Bent MJ, Dubbink HJ, Sanson M et al (2009) 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 27:5881–5886CrossRefPubMedGoogle Scholar
  30. 30.
    van den Bent MJ, Dubbink HJ, Marie Y et al (2010) IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res 16:1597–1604CrossRefPubMedGoogle Scholar
  31. 31.
    Weller M, Berger H, Hartmann C et al (2007) Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker? Clin Cancer Res 13:6933–6937CrossRefPubMedGoogle Scholar
  32. 32.
    Weller M, Felsberg J, Hartmann C et al (2009) 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 27:5743–5750CrossRefPubMedGoogle Scholar
  33. 33.
    Weller M, Stupp R, Reifenberger G et al (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nature Rev Neurol 6:39–51CrossRefGoogle Scholar
  34. 34.
    Wick A, Pascher C, Wick W et al (2009) Rechallenge with temozolomide in patients with recurrent gliomas. J Neurol 256:734–741CrossRefPubMedGoogle Scholar
  35. 35.
    Wick W, Hartmann C, Engel C et al (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. J Clin Oncol 27:5874–5880CrossRefPubMedGoogle Scholar
  36. 36.
    Wick W, Engel C, Combs SE et al (2010) NOA-08 randomized phase III trial of 1-week-on/1-week-off temozolomide versus involved field radiotherapy in elderly (older than age 65) patients with newly diagnosed anaplastic astrocytoma or glioblastoma (Methusalem). J Clin Oncol 28:7s (suppl; abstr. LBA2001)Google Scholar
  37. 37.
    Wick W, Puduvalli VK, Chamberlain M et al (2010) Enzastaurin versus lomustine in the treatment of recurrent intracranial glioblastoma: a phase III study. J Clin Oncol 28:1168–1174CrossRefPubMedGoogle Scholar
  38. 38.
    Wick W, Weller M, van den Bent M, Stupp R (2010) Bevacizumab and reccurent malignant gliomas: a European perspective. J Clin Oncol 28:e188–189Google Scholar
  39. 39.
    Yung WKA, Prados MD, Yaga-Tur R et al (1999) Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17:2762–2771PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ghazaleh Tabatabai
    • 1
    Email author
  • Roger Stupp
    • 2
  • Martin J. van den Bent
    • 3
  • Monika E. Hegi
    • 2
  • Jörg C. Tonn
    • 4
  • Wolfgang Wick
    • 5
  • Michael Weller
    • 1
  1. 1.Department of NeurologyUniversity Hospital ZurichZurichSwitzerland
  2. 2.Department of NeurosurgeryCentre Hospitalier Universitaire Vaudois and University of LausanneLausanneSwitzerland
  3. 3.Neuro-Oncology Unit, Daniel de Hoed Cancer Centre/ErasmusUniversity Hospital RotterdamRotterdamThe Netherlands
  4. 4.Department of NeurosurgeryUniversity of Munich LMUMunichGermany
  5. 5.Department of Neurooncology, Neurology Clinic and National Center for Tumor DiseaseUniversity of HeidelbergHeidelbergGermany

Personalised recommendations