Tumor Biology

, Volume 37, Issue 1, pp 87–96 | Cite as

MGMT testing allows for personalised therapy in the temozolomide era



Adjuvant temozolomide (TMZ)-based chemoradiation is the standard of care for most glioblastoma patients (GBMs); however, a large proportion of these patients do not respond to TMZ. Silencing of the O6-methylguanine-DNA methyltransferase (MGMT) promoter is thought to induce chemosensitivity, and testing for methylation may allow for patient stratification; however, this has yet to become routine clinical practice despite an abundance of literature on the subject. The databases PubMed, Embase, The Cochrane Library, Science Direct and Medline were searched for relevant articles published between 1999 and 2015. Articles utilising MGMT testing in glioblastomas, and treatment of glioblastomas with temozolomide were assessed. Immunohistochemistry, methylation-specific PCR (MSP), reverse transcriptase PCR, pyrosequencing and bisulphite sequencing were the main testing methods identified. Nested-MSP techniques produced poor correlation with survival, whilst bisulphite sequencing showed no evident benefit over MSP. Testing is limited by sample quality and contamination; however, efforts are made to minimise this. Strong evidence for MGMT-based personalised therapy was presented in the elderly but remains controversial in the entire GBM population. MGMT testing presents many obstacles yet to be overcome, and these warrant attention prior to the routine implementation of MGMT testing to aid decision making in GBMs. However, there is evidence to support its use, particularly in the elderly.


Glioma Temozolomide MGMT 





Glioblastoma multiforme


O6-Methylgaunine-DNA methyltransferase




Overall survival


Progression-free survival




Polymerase chain reaction


Methylation-specific polymerase chain reaction


Formalin-fixed paraffin-embedded

Stupp protocol

Concomitant temozolomide and radiotherapy + adjuvant temozolomide


European Organisation for Research and Treatment of Cancer


National Cancer Institute of Canada


Radiation Therapy Oncology Group


Karnofsky performance status


  1. 1.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.CrossRefPubMedGoogle Scholar
  2. 2.
    Hart MG, Garside R, Rogers G, Stein K, Grant R. Temozolomide for high grade glioma. Cochrane Database Syst Rev. 2013;4:Cd007415.Google Scholar
  3. 3.
    Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13:707–15.CrossRefPubMedGoogle Scholar
  4. 4.
    Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, 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. 2012;13:916–26.CrossRefPubMedGoogle Scholar
  5. 5.
    Niewald M, Berdel C, Fleckenstein J, Licht N, Ketter R, Rube C. Toxicity after radiochemotherapy for glioblastoma using temozolomide—a retrospective evaluation. Radiat Oncol. 2011;6:141.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Zhang M, Chakravarti A. Novel radiation-enhancing agents in malignant gliomas. Semin Radiat Oncol. 2006;16:29–37.CrossRefPubMedGoogle Scholar
  7. 7.
    Sengupta S, Marrinan J, Frishman C, Sampath P. Impact of temozolomide on immune response during malignant glioma chemotherapy. Clin Dev Immunol. 2012;2012:831090.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cankovic M, Nikiforova MN, Snuderl M, Adesina AM, Lindeman N, Wen PY, et al. The role of MGMT testing in clinical practice: a report of the association for molecular pathology. J Mol Diagn. 2013;15:539–55.CrossRefPubMedGoogle Scholar
  9. 9.
    Nehru GA, Pai R, Samuel P, Chacko AG, Chacko G. Status of O6 -methylguanine-DNA methyltransferase [MGMT] gene promoter methylation among patients with glioblastomas from India. Neurol India. 2012;60:481–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Balana C, Carrato C, Ramirez JL, Cardona AF, Berdiel M, Sanchez JJ, et al. Tumour and serum MGMT promoter methylation and protein expression in glioblastoma patients. Clin Transl Oncol: Off Publ Fed Span Oncol Soc Ntnl Cancer Inst Mex. 2011;13:677–85.CrossRefGoogle Scholar
  11. 11.
    Mikeska T, Bock C, El-Maarri O, Hubner A, Ehrentraut D, Schramm J, et al. Optimization of quantitative MGMT promoter methylation analysis using pyrosequencing and combined bisulfite restriction analysis. J Mol Diagn: JMD. 2007;9:368–81.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Preusser M. MGMT analysis at DNA, RNA and protein levels in glioblastoma tissue. Histol Histopathol. 2009;24:511–8.PubMedGoogle Scholar
  13. 13.
    Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, 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: Off J Am Assoc Cancer Res. 2004;10:1871–4.CrossRefGoogle Scholar
  14. 14.
    Felsberg J, Rapp M, Loeser S, Fimmers R, Stummer W, Goeppert M, et al. Prognostic significance of molecular markers and extent of resection in primary glioblastoma patients. Clin Cancer Res: Off J Am Assoc Cancer Res. 2009;15:6683–93.CrossRefGoogle Scholar
  15. 15.
    Miyazaki M, Nishihara H, Terasaka S, Kobayashi H, Yamaguchi S, Ito T, et al. Immunohistochemical evaluation of O6 -methylguanine DNA methyltransferase (MGMT) expression in 117 cases of glioblastoma. Neuropathol: Off J Japan Soc Neuropathol. 2014;34:268–76.CrossRefGoogle Scholar
  16. 16.
    Ening G, Osterheld F, Capper D, Schmieder K, Brenke C. Risk factors for glioblastoma therapy associated complications. Clin Neurol Neurosurg. 2015;134:55–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. Mgmt gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.CrossRefPubMedGoogle Scholar
  18. 18.
    Tang K, Jin Q, Yan W, Zhang W, You G, Liu Y, et al. Clinical correlation of MGMT protein expression and promoter methylation in chinese glioblastoma patients. Med Oncol (Northwood, London, England). 2012;29:1292–6.CrossRefGoogle Scholar
  19. 19.
    Della Puppa A, Persano L, Masi G, Rampazzo E, Sinigaglia A, Pistollato F, et al. Mgmt expression and promoter methylation status may depend on the site of surgical sample collection within glioblastoma: a possible pitfall in stratification of patients? J Neuro-Oncol. 2012;106:33–41.CrossRefGoogle Scholar
  20. 19.
    Sonoda Y, Yokosawa M, Saito R, Kanamori M, Yamashita Y, Kumabe T, et al. O(6)-methylguanine DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression is correlated with progression-free survival in patients with glioblastoma. Int J Clin Oncol. 2010;15:352–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Watanabe R, Nakasu Y, Tashiro H, Mitsuya K, Ito I, Nakasu S, et al. O6-methylguanine DNA methyltransferase expression in tumor cells predicts outcome of radiotherapy plus concomitant and adjuvant temozolomide therapy in patients with primary glioblastoma. Brain Tumor Pathol. 2011;28:127–35.CrossRefPubMedGoogle Scholar
  22. 22.
    Quillien V, Lavenu A, Karayan-Tapon L, Carpentier C, Labussiere M, Lesimple T, et al. Comparative assessment of 5 methods (methylation-specific polymerase chain reaction, methylight, pyrosequencing, methylation-sensitive high-resolution melting, and immunohistochemistry) to analyze O6-methylguanine-DNA-methyltranferase in a series of 100 glioblastoma patients. Cancer. 2012;118:4201–11.CrossRefPubMedGoogle Scholar
  23. 23.
    Karim KA, El Mahdy MM, Wahab MMA, Ei Arab LRE, El Shehaby A, Raouf SA. Temozolomide and radiotherapy in newly diagnosed glioblastoma patients: O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status and ki-67 as biomarkers for survival and response to treatment. Chinese-German J Clin Oncol. 2012;11:168–76.CrossRefGoogle Scholar
  24. 24.
    Grasbon-Frodl EM, Kreth FW, Ruiter M, Schnell O, Bise K, Felsberg J, et al. Intratumoral homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas. Int J Cancer J Int Du Cancer. 2007;121:2458–64.CrossRefGoogle Scholar
  25. 25.
    Mellai M, Caldera V, Annovazzi L, Chio A, Lanotte M, Cassoni P, et al. Mgmt promoter hypermethylation in a series of 104 glioblastomas. Cancer Genomics Proteomics. 2009;6:219–27.PubMedGoogle Scholar
  26. 26.
    Preusser M, Charles Janzer R, Felsberg J, Reifenberger G, Hamou MF, Diserens AC, et al. Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker. Brain pathol (Zurich, Switzerland). 2008;18:520–32.Google Scholar
  27. 27.
    Karayan-Tapon L, Quillien V, Guilhot J, Wager M, Fromont G, Saikali S, et al. Prognostic value of O6-methylguanine-DNA methyltransferase status in glioblastoma patients, assessed by five different methods. J Neuro-Oncol. 2010;97:311–22.CrossRefGoogle Scholar
  28. 28.
    Laigle-Donadey F, Figarella-Branger D, Chinot O, Taillandier L, Cartalat-Carel S, Honnorat J, et al. Up-front temozolomide in elderly patients with glioblastoma. J Neuro-Oncol. 2010;99:89–94.CrossRefGoogle Scholar
  29. 29.
    Maxwell JA, Johnson SP, Quinn JA, McLendon RE, Ali-Osman F, Friedman AH, et al. Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma. Mol Cancer Ther. 2006;5:2531–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Buttarelli FR, Massimino M, Antonelli M, Lauriola L, Nozza P, Donofrio V, et al. Evaluation status and prognostic significance of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in pediatric high grade gliomas. Child’s Nerv Syst: ChNS: Off J Int Soc Pediatr Neurosurg. 2010;26:1051–6.CrossRefGoogle Scholar
  31. 31.
    Christmann M, Nagel G, Horn S, Krahn U, Wiewrodt D, Sommer C, et al. Mgmt activity, promoter methylation and immunohistochemistry of pretreatment and recurrent malignant gliomas: a comparative study on astrocytoma and glioblastoma. Int J Cancer J Int Du Cancer. 2010;127:2106–18.CrossRefGoogle Scholar
  32. 32.
    Nakasu S, Fukami T, Baba K, Matsuda M. Immunohistochemical study for O6-methylguanine-DNA methyltransferase in the non-neoplastic and neoplastic components of gliomas. J Neuro-Oncol. 2004;70:333–40.CrossRefGoogle Scholar
  33. 33.
    Nakagawa T, Ido K, Sakuma T, Takeuchi H, Sato K, Kubota T. Prognostic significance of the immunohistochemical expression of O6-methylguanine-DNA methyltransferase, p-glycoprotein, and multidrug resistance protein-1 in glioblastomas. Neuropathol: Off J Japan Soc Neuropathol. 2009;29:379–88.CrossRefGoogle Scholar
  34. 34.
    Mellai M, Monzeglio O, Piazzi A, Caldera V, Annovazzi L, Cassoni P, et al. Mgmt promoter hypermethylation and its associations with genetic alterations in a series of 350 brain tumors. J Neuro-Oncol. 2012;107:617–31.CrossRefGoogle Scholar
  35. 35.
    Araki Y, Mizoguchi M, Yoshimoto K, Shono T, Amano T, Nakamizo A, et al. Quantitative digital assessment of MGMT immunohistochemical expression in glioblastoma tissue. Brain Tumor Pathol. 2011;28:25–31.CrossRefPubMedGoogle Scholar
  36. 36.
    Cankovic M, Mikkelsen T, Rosenblum ML, Zarbo RJ. A simplified laboratory validated assay for MGMT promoter hypermethylation analysis of glioma specimens from formalin-fixed paraffin-embedded tissue. Lab Investig; J Tech Methods Pathol. 2007;87:392–7.Google Scholar
  37. 37.
    Cohen KJ, Pollack IF, Zhou T, Buxton A, Holmes EJ, Burger PC, et al. Temozolomide in the treatment of high-grade gliomas in children: a report from the children’s oncology group. Neuro-Oncology. 2011;13:317–23.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Parkinson JF, Wheeler HR, Clarkson A, McKenzie CA, Biggs MT, Little NS, et al. Variation of o(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in serial samples in glioblastoma. J Neuro-Oncol. 2008;87:71–8.CrossRefGoogle Scholar
  39. 39.
    Darst RP, Pardo CE, Ai L, Brown KD, Kladde MP: Bisulfite sequencing of DNA. Current protocols in molecular biology / edited by Frederick M Ausubel [et al.] 2010;Chapter 7:Unit 7.9.1-17.Google Scholar
  40. 40.
    Mikeska T, Bock C. O EI-M, Hubner A, Ehrentraut D, Schramm J, Felsberg J, Kahl P, Buttner R, Pietsch T, Waha A: optimization of quantitative MGMT promoter methylation analysis using pyrosequencing and combined bisulfite restriction analysis. J Mol Diagn. 2007;9:368–81.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Shaw RJ, Akufo-Tetteh EK, Risk JM, Field JK, Liloglou T. Methylation enrichment pyrosequencing: combining the specificity of MSP with validation by pyrosequencing. Nucleic Acids Res. 2006;34, e78.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Schlosser S, Wagner S, Mu Hlisch J, Hasselblatt M, Gerss J, Wolff JEA, et al. MGMT as a potential stratification marker in relapsed high-grade glioma of children: the HIT-GBM experience. Pediatric Blood Cancer. 2010;54:228–37.PubMedGoogle Scholar
  43. 43.
    Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 1999;59:793–7.PubMedGoogle Scholar
  44. 44.
    Juratli TA, Kirsch M, Geiger K, Klink B, Leipnitz E, Pinzer T, et al. The prognostic value of IDH mutations and MGMT promoter status in secondary high-grade gliomas. J Neuro-Oncol. 2012;110:325–33.CrossRefGoogle Scholar
  45. 45.
    Eoli M, Menghi F, Bruzzone MG, De Simone T, Valletta L, Pollo B, et al. Methylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival. Clin Cancer Res: Off J Am Assoc Cancer Res. 2007;13:2606–13.CrossRefGoogle Scholar
  46. 46.
    Melguizo C, Prados J, Gonzalez B, Ortiz R, Concha A, Alvarez PJ, et al. MGMT promoter methylation status and MGMT and CD133 immunohistochemical expression as prognostic markers in glioblastoma patients treated with temozolomide plus radiotherapy. J Transl Med. 2012;10:250.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kreth S, Thon N, Eigenbrod S, Lutz J, Ledderose C, Egensperger R, et al. O-methylguanine-DNA methyltransferase (MGMT) mRNA expression predicts outcome in malignant glioma independent of MGMT promoter methylation. PLoS One. 2011;6, e17156.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Everhard S, Tost J, El Abdalaoui H, Criniere E, Busato F, Marie Y, et al. Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas. Neuro-Oncology. 2009;11:348–56.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Malley DS, Hamoudi RA, Kocialkowski S, Pearson DM, Collins VP, Ichimura K. A distinct region of the MGMT CpG island critical for transcriptional regulation is preferentially methylated in glioblastoma cells and xenografts. Acta Neuropathol. 2011;121:651–61.CrossRefPubMedGoogle Scholar
  50. 50.
    Reifenberger G, Hentschel B, Felsberg J, Schackert G, Simon M, Schnell O, et al. Predictive impact of MGMT promoter methylation in glioblastoma of the elderly. Int J Cancer J Int Du Cancer. 2012;131:1342–50.CrossRefGoogle Scholar
  51. 51.
    Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, et al. Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer. 2009;101:124–31.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Christians A, Hartmann C, Benner A, Meyer J, von Deimling A, Weller M, et al. Prognostic value of three different methods of MGMT promoter methylation analysis in a prospective trial on newly diagnosed glioblastoma. PLoS One. 2012;7, e33449.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Uno M, Oba-Shinjo SM, Camargo AA, Moura RP, Aguiar PH, Cabrera HN, et al. Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma. Clinics (Sao Paulo, Brazil). 2011;66:1747–55.CrossRefGoogle Scholar
  54. 54.
    Parrella P, La Torre A, Copetti M, Valori VM, Barbano R, Notarangelo A, et al. High specificity of quantitative methylation-specific PCR analysis for MGMT promoter hypermethylation detection in gliomas. J Biomed Biotechnol. 2009;2009.Google Scholar
  55. 55.
    Hsu CY, Ho HL, Lin SC, Chang-Chien YC, Chen MH, Hsu SP, et al. Prognosis of glioblastoma with faint MGMT methylation-specific PCR product. J Neuro-Oncol. 2015;122:179–88.CrossRefGoogle Scholar
  56. 56.
    Vassella E, Vajtai I, Bandi N, Arnold M, Kocher V, Mariani L. Primer extension based quantitative polymerase chain reaction reveals consistent differences in the methylation status of the MGMT promoter in diffusely infiltrating gliomas (who grade II-IV) of adults. J Neuro-Oncol. 2011;104:293–303.CrossRefGoogle Scholar
  57. 57.
    Costa BM, Caeiro C, Guimaraes I, Martinho O, Jaraquemada T, Augusto I, et al. Prognostic value of MGMT promoter methylation in glioblastoma patients treated with temozolomide-based chemoradiation: a Portuguese multicentre study. Oncol Rep. 2010;23:1655–62.PubMedGoogle Scholar
  58. 58.
    Okita Y, Narita Y, Miyakita Y, Ohno M, Fukushima S, Kayama T, et al. Pathological findings and prognostic factors in recurrent glioblastomas. Brain Tumor Pathol. 2012;29:192–200.CrossRefPubMedGoogle Scholar
  59. 59.
    Singh G, Mallick S, Sharma V, Joshi N, Purkait S, Jha P, et al. A study of clinico-pathological parameters and O6 - methylguanine DNA methyltransferase (MGMT) promoter methylation status in the prognostication of gliosarcoma. Neuropathol: Off J Japan Soc Neuropathol. 2012;32:534–42.CrossRefGoogle Scholar
  60. 60.
    Hattermann K, Mehdorn HM, Mentlein R, Schultka S, Held-Feindt J. A methylation-specific and sybr-green-based quantitative polymerase chain reaction technique for O6-methylguanine DNA methyltransferase promoter methylation analysis. Anal Biochem. 2008;377:62–71.CrossRefPubMedGoogle Scholar
  61. 61.
    Vlassenbroeck I, Califice S, Diserens AC, Migliavacca E, Straub J, Di Stefano I, et al. Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma. J Mol Diagn: JMD. 2008;10:332–7.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Lavon I, Refael M, Zelikovitch B, Shalom E, Siegal T. Serum DNA can define tumor-specific genetic and epigenetic markers in gliomas of various grades. Neuro-Oncology. 2010;12:173–80.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Morandi L, Franceschi E, de Biase D, Marucci G, Tosoni A, Ermani M, et al. Promoter methylation analysis of O6-methylguanine-DNA methyltransferase in glioblastoma: detection by locked nucleic acid based quantitative PCR using an imprinted gene (SNURF) as a reference. BMC Cancer. 2010;10.Google Scholar
  64. 64.
    Reifenberger G, Hentschel B, Felsberg J, Schackert G, Simon M, Schnell O, et al. Mgmt promoter methylation is a predictive molecular marker in older patients with glioblastoma. Clin Neuropathol. 2011;30:260–1.Google Scholar
  65. 65.
    Shen D, Liu T, Lin Q, Lu X, Wang Q, Lin F, et al. Mgmt promoter methylation correlates with an overall survival benefit in Chinese high-grade glioblastoma patients treated with radiotherapy and alkylating agent-based chemotherapy: a single-institution study. PLoS One. 2014;9, e107558.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Felsberg J, Thon N, Eigenbrod S, Hentschel B, Sabel MC, Westphal M, 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 J Int Du Cancer. 2011;129:659–70.CrossRefGoogle Scholar
  67. 67.
    Quillien V, Lavenu A, Sanson M, Legrain M, Dubus P, Karayan-Tapon L, et al. Outcome-based determination of optimal pyrosequencing assay for MGMT methylation detection in glioblastoma patients. J Neuro-Oncol. 2014;116:487–96.CrossRefGoogle Scholar
  68. 68.
    Havik AB, Brandal P, Honne H, Dahlback HS, Scheie D, Hektoen M, et al. Mgmt promoter methylation in gliomas-assessment by pyrosequencing and quantitative methylation-specific PCR. J Transl Med. 2012;10:36.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Bady P, Sciuscio D, Diserens A-C, Bloch J, van den Bent MJ, Marosi C, 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. 2012;124:547–60.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Thon N, Eigenbrod S, Grasbon-Frodl EM, Lutz J, Kreth S, Popperl G, et al. Predominant influence of MGMT methylation in non-resectable glioblastoma after radiotherapy plus temozolomide. J Neurol Neurosurg Psychiatry. 2011;82:441–6.CrossRefPubMedGoogle Scholar
  71. 71.
    Eigenbrod S, Trabold R, Brucker D, Eros C, Egensperger R, La Fougere C, et al. Molecular stereotactic biopsy technique improves diagnostic accuracy and enables personalized treatment strategies in glioma patients. Acta Neurochir. 2014;156:1427–40.CrossRefPubMedGoogle Scholar
  72. 72.
    Lalezari S, Chou AP, Tran A, Solis OE, Khanlou N, Chen W, et al. Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome. Neuro-Oncology. 2013;15:370–81.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Yachi K, Watanabe T, Ohta T, Fukushima T, Yoshino A, Ogino A, et al. Relevance of MSP assay for the detection of MGMT promoter hypermethylation in glioblastomas. Int J Oncol. 2008;33:469–75.PubMedGoogle Scholar
  74. 74.
    Sasai K, Nodagashira M, Nishihara H, Aoyanagi E, Wang L, Katoh M, et al. Careful exclusion of non-neoplastic brain components is required for an appropriate evaluation of O6-methylguanine-DNA methyltransferase status in glioma: relationship between immunohistochemistry and methylation analysis. Am J Surg Pathol. 2008;32:1220–7.CrossRefPubMedGoogle Scholar
  75. 75.
    Tuononen K, Tynninen O, Sarhadi VK, Tyybakinoja A, Lindlof M, Antikainen M, et al. The hypermethylation of the O6-methylguanine-DNA methyltransferase gene promoter in gliomas—correlation with array comparative genome hybridization results and IDH1 mutation. Genes, Chromosome Cancer. 2012;51:20–9.CrossRefGoogle Scholar
  76. 76.
    Preusser M, Berghoff AS, Manzl C, Filipits M, Weinhausel A, Pulverer W, et al. Clinical neuropathology practice news 1–2014: pyrosequencing meets clinical and analytical performance criteria for routine testing of MGMT promoter methylation status in glioblastoma. Clin Neuropathol. 2014;33:6–14.CrossRefPubMedGoogle Scholar
  77. 77.
    Shamsara J, Sharif S, Afsharnezhad S, Lotfi M, Raziee HR, Ghaffarzadegan K, et al. Association between MGMT promoter hypermethylation and p53 mutation in glioblastoma. Cancer Investig. 2009;27:825–9.CrossRefGoogle Scholar
  78. 78.
    Salvati M, Pichierri A, Piccirilli M, Brunetto GMF, D’Elia A, Artizzu S, et al. Extent of tumor removal and molecular markers in cerebral glioblastoma: a combined prognostic factors study in a surgical series of 105 patients—clinical article. J Neurosurg. 2012;117:204–11.CrossRefPubMedGoogle Scholar
  79. 79.
    Lattanzio L, Borgognone M, Mocellini C, Giordano F, Favata E, Fasano G, et al. Mgmt promoter methylation and glioblastoma: a comparison of analytical methods and of tumor specimens. Int J Biol Mark. 2015;30:e208–16.Google Scholar
  80. 80.
    Hamilton MG, Roldan G, Magliocco A, McIntyre JB, Parney I, Easaw JC. Determination of the methylation status of MGMT in different regions within glioblastoma multiforme. J Neuro-Oncol. 2011;102:255–60.CrossRefGoogle Scholar
  81. 81.
    Iaccarino C, Orlandi E, Ruggeri F, Nicoli D, Torricelli F, Maggi M, et al. Prognostic value of MGMT promoter status in non-resectable glioblastoma after adjuvant therapy. Clin Neurol Neurosurg. 2015;132:1–8.CrossRefPubMedGoogle Scholar
  82. 82.
    Weller M, Tabatabai G, Kastner B, Felsberg J, Steinbach JP, Wick A, et al. Mgmt promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the director trial. Clin Cancer Res: Off J Am Assoc Cancer Res. 2015;21:2057–64.CrossRefGoogle Scholar
  83. 83.
    Brandes AA, Franceschi E, Tosoni A, Bartolini S, Bacci A, Agati R, et al. O(6)-methylguanine DNA-methyltransferase methylation status can change between first surgery for newly diagnosed glioblastoma and second surgery for recurrence: clinical implications. Neuro-Oncology. 2010;12:283–8.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Barault L, Amatu A, Bleeker FE, Moutinho C, Falcomatà C, Fiano V, et al. Digital PCR quantification of MGMT methylation refines prediction of clinical benefit from alkylating agents in glioblastoma and metastatic colorectal cancer. Ann Oncol. 2015. doi: 10.1093/annonc/mdv272.
  85. 85.
    Fiano V, Trevisan M, Trevisan E, Senetta R, Castiglione A, Sacerdote C, et al. Mgmt promoter methylation in plasma of glioma patients receiving temozolomide. J Neuro-Oncol. 2014;117:347–57.CrossRefGoogle Scholar
  86. 86.
    Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra224.CrossRefGoogle Scholar
  87. 87.
    Batchelor T, Loeffler J, Eichler A, Shihm H, Wen P: Management of glioblastoma in elderly patients: UpToDate. Waltham MA, UpToDate, 2014.Google Scholar
  88. 88.
    Piccirilli M, Bistazzoni S, Gagliardi FM, Landi A, Santoro A, Giangaspero F, et al. Treatment of glioblastoma multiforme in elderly patients. Clinico-therapeutic remarks in 22 patients older than 80 years. Tumori. 2006;92:98–103.PubMedGoogle Scholar
  89. 89.
    Norden AD, Lesser GJ, Drappatz J, Ligon KL, Hammond SN, Lee EQ, et al. Phase 2 study of dose-intense temozolomide in recurrent glioblastoma. Neuro-Oncology. 2013;15:930–5.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Gallego Perez-Larraya J, Ducray F, Chinot O, Catry-Thomas I, Taillandier L, Guillamo JS, et al. Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an anocef phase ii trial. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:3050–5.CrossRefGoogle Scholar
  91. 91.
    Minniti G, Salvati M, Arcella A, Buttarelli F, D’Elia A, Lanzetta G, et al. Correlation between O6-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide. J Neuro-Oncol. 2011;102:311–6.CrossRefGoogle Scholar
  92. 92.
    Sijben AE, McIntyre JB, Roldan GB, Easaw JC, Yan E, Forsyth PA, et al. Toxicity from chemoradiotherapy in older patients with glioblastoma multiforme. J Neuro-Oncol. 2008;89:97–103.CrossRefGoogle Scholar
  93. 93.
    Takahashi Y, Nakamura H, Makino K, Hide T, Muta D, Kamada H, et al. Prognostic value of isocitrate dehydrogenase 1, O6-methylguanine-DNA methyltransferase promoter methylation, and 1p19q co-deletion in japanese malignant glioma patients. World J Surg Oncol. 2013;11:284.Google Scholar
  94. 94.
    Molenaar RJ, Verbaan D, Lamba S, Zanon C, Jeuken JW, Boots-Sprenger SH, et al. The combination of idh1 mutations and MGMT methylation status predicts survival in glioblastoma better than either idh1 or mgmt alone. Neuro-Oncology. 2014;16:1263–73.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Colman H, Zhang L, Sulman EP, McDonald JM, Shooshtari NL, Rivera A, et al. A multigene predictor of outcome in glioblastoma. Neuro-Oncology. 2010;12:49–57.CrossRefPubMedGoogle Scholar
  96. 96.
    Donson AM, Addo-Yobo SO, Handler MH, Gore L, Foreman NK. Mgmt promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma. Pediatric Blood Cancer. 2007;48:403–7.CrossRefPubMedGoogle Scholar
  97. 97.
    Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol. 2015;129:669–78.CrossRefPubMedGoogle Scholar
  98. 98.
    Clarke JL, Iwamoto FM, Sul J, Panageas K, Lassman AB, DeAngelis LM, et al. Randomized phase ii trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol: Off J Am Soc Clin Oncol. 2009;27:3861–7.CrossRefGoogle Scholar
  99. 99.
    Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi M, Jaeckle KA, et al. Rtog 0525: a randomized phase iii trial comparing standard adjuvant temozolomide (TMZ) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (GBM). J Clin Oncol. 2011;29.Google Scholar
  100. 100.
    Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (centric eortc 26071–22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1100–8.CrossRefPubMedGoogle Scholar
  101. 101.
    Nabors LB, Fink KL, Mikkelsen T, Grujicic D, Tarnawski R. Nam do H, Mazurkiewicz M, Salacz M, Ashby L, Zagonel V, Depenni R, Perry JR, Hicking C, Picard M, Hegi ME, Lhermitte B, Reardon DA: two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II core study. Neuro-Oncology. 2015;17:708–17.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Applied Radiation Therapy TrinityTrinity College DublinDublinIreland
  2. 2.Discipline of Radiation TherapyTrinity Centre for Health SciencesDublin 8Ireland

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