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Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis

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Abstract

Epigenetic silencing of the O6-methylguanine-DNA methyltransferase (MGMT) gene is associated with improved survival in patients with high-grade gliomas (HGG), with varying estimates of magnitude. The objective of this meta-analysis is to determine the prognostic value of MGMT silencing, and assess its predictive value by treatment type. MEDLINE and EMBASE databases were searched for studies relating to gliomas and MGMT. Studies reporting overall survival (OS) by MGMT status in patients with HGG were considered potentially eligible. We excluded studies that did not control for potential confounding variables. A meta-analysis of studies was performed via random-effects modelling. Subgroup meta-analyses by treatment were performed according to a priori hypotheses. Twenty studies were ultimately eligible, including 2,018 patients. In the pooled analysis, MGMT silencing was associated with improved OS (HR = 0.436; 95% CI: 0.333–0.571; P < 0.001). The prognostic utility of MGMT status varies significantly by treatment type (P = 0.001): the HR for OS for MGMT silenced tumors is 0.190 (0.047–0.770), 0.403 (0.282–0.576), 0.743 (0.579–0.954), and 1.070 (0.722–1.585) for studies using surgery plus the addition of either: chemotherapy (CT), chemoradiotherapy (CRT), radiotherapy (RT), and nothing (surgery alone), respectively. Epigenetic silencing of MGMT is associated with markedly improved survival in patients with HGG who receive adjuvant therapy. MGMT silencing serves as a predictive marker, with the largest benefit seen in patients receiving CT as a component of adjuvant treatment, an intermediate benefit in patients receiving adjuvant RT, and no evidence to support benefit in those receiving surgery alone.

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References

  1. Curran WJ Jr, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, Chang CH, Rotman M, Asbell SO, Krisch RE, Nelson DF (1993) Recursive partitioning analysis of prognostic factors in three radiation therapy oncology group malignant glioma trials. J Natl Cancer Inst 85:704–710. doi:10.1093/jnci/85.9.704

    Article  PubMed  Google Scholar 

  2. Olson R, Tyldesley S, Carolan H, Parkinson M, Chhanabhai T, McKenzie M (2010) Prospective comparison of the prognostic utility of the Mini Mental State Examination and the Montreal Cognitive Assessment in patients with brain metastases. Support Care Cancer. doi:10.1007/s00520-010-1028-1

  3. Hegi ME, Diserens A, Gorlia T, Hamou M, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JEC, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. doi:10.1056/NEJMoa043331

    Article  PubMed  CAS  Google Scholar 

  4. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797

    PubMed  CAS  Google Scholar 

  5. Hall EJ, Giaccia AJ (2006) Radiobiology for the radiologist. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  6. Brell M, Ibanez J, Tortosa A (2011) O6-methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction. BMC Cancer 11:35. doi:10.1186/1471-2407-11-35

    Article  PubMed  Google Scholar 

  7. Zawlik I, Vaccarella S, Kita D, Mittelbronn M, Franceschi S, Ohgaki H (2009) Promoter methylation and polymorphisms of the MGMT gene in glioblastomas: a population-based study. Neuroepidemiology 32:21–29. doi:10.1159/000170088

    Article  PubMed  Google Scholar 

  8. Mineura K, Yanagisawa T, Watanabe K, Kowada M, Yasui N (1996) Human brain tumor O6-methylguanine-DNA methyltransferase mRNA and its significance as an indicator of selective chloroethylnitrosourea. Chemotherapy 69:420–425. doi:10.1002/(SICI)1097-0215(19961021)69:5<420:AID-IJC12>3.0.CO;2-6

    CAS  Google Scholar 

  9. Esteller M, Herman JG (2004) Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer. Oncogene 23:1–8. doi:10.1038/sj.onc.1207316

    Article  PubMed  CAS  Google Scholar 

  10. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Annals of Internal Medicine 151:W-65, W-94. doi:10.1059/0003-4819-151-4-200908180-00136

  11. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB, for the Meta-Analysis of Observational Studies in Epidemiology Group (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 283:2008–2012. doi:10.1001/jama.283.15.2008

    Article  PubMed  CAS  Google Scholar 

  12. Duchateau L, Collette L, Sylvester R, Pignon JP (2000) Estimating number of events from the Kaplan–Meier curve for incorporation in a literature-based meta-analysis: what you don’t see you can’t get!. Biometrics 56:886–892

    Article  PubMed  CAS  Google Scholar 

  13. Michiels S, Piedbois P, Burdett S, Syz N, Stewart L, Pignon JP (2005) Meta-analysis when only the median survival times are known: a comparison with individual patient data results. Int J Technol Assess Health Care 21:119–125

    Article  PubMed  Google Scholar 

  14. Hirooka T, Hamada C, Yoshimura I (2009) A note on estimating treatment effect for time-to-event data in a literature-based meta-analysis. Methods Inf Med 48:104–112. doi:10.3414/ME0535

    PubMed  Google Scholar 

  15. Gorlia T, van den Bent MJ, Hegi ME, Mirimanoff RO, Weller M, Cairncross JG, Eisenhauer E, Belanger K, Brandes AA, Allgeier A, Lacombe D, Stupp R (2008) Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol 9:29–38. doi:10.1016/S1470-2045(07)70384-4

    Article  PubMed  Google Scholar 

  16. Hopkins WG (2007) A spreadsheet for deriving a confidence interval, mechanistic inference and clinical inference from a p value. Sportscience 11:16–20

    Google Scholar 

  17. Costa B, Caeiro C, Guimarães I, Martinho O, Jaraquemada T, Augusto I, Castro L, Osório L, Linhares P, Honavar M, Resende M, Braga F, Silva A, Pardal F, Amorim J, Nabiço R, Almeida R, Alegria C, Pires M, Pinheiro C, Carvalho E, Lopes JM, Costa P, Damasceno M, Reis RM (2010) Prognostic value of MGMT promoter methylation in glioblastoma patients treated with temozolomide-based chemoradiation: a Portuguese multicentre study. Oncol Rep 23:1655–1662. doi:10.3892/or_00000808

    PubMed  CAS  Google Scholar 

  18. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558. doi:10.1002/sim.1186

    Article  PubMed  Google Scholar 

  19. Brell M, Tortosa A, Verger E, Gil JM, Vinolas N, Villa S, Acebes JJ, Caral L, Pujol T, Ferrer I, Ribalta T, Graus F (2005) Prognostic significance of O6-methylguanine-DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression in anaplastic gliomas. Clin Cancer Res 11:5167–5174. doi:10.1158/1078-0432.CCR-05-0230

    Article  PubMed  CAS  Google Scholar 

  20. Schaich M, Kestel L, Pfirrmann M, Robel K, Illmer T, Kramer M, Dill C, Ehninger G, Schackert G, Krex D (2009) A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol 20:175–181. doi:10.1093/annonc/mdn548

    Article  PubMed  CAS  Google Scholar 

  21. Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, Bertorelle R, Bartolini S, Calbucci F, Andreoli A, Frezza G, Leonardi M, Spagnolli F, Ermani M (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 26:2192–2197. doi:10.1200/JCO.2007.14.8163

    Article  PubMed  Google Scholar 

  22. Cao VT, Jung TY, Jung S, Jin SG, Moon KS, Kim IY, Kang SS, Park CS, Lee KH, Chae HJ (2009) The correlation and prognostic significance of MGMT promoter methylation and MGMT protein in glioblastomas. Neurosurgery 65:866–875; discussion 875. doi:10.1227/01.NEU.0000357325.90347.A1

    Google Scholar 

  23. Clarke JL, Iwamoto FM, Sul J, Panageas K, Lassman AB, DeAngelis LM, Hormigo A, Nolan CP, Gavrilovic I, Karimi S, Abrey LE (2009) Randomized Phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 27:3861–3867. doi:10.1200/JCO.2008.20.7944

    Article  PubMed  CAS  Google Scholar 

  24. Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, Crooks D, Husband D, Shenoy A, Brodbelt A, Wong H, Liloglou T, Haylock B, Walker C (2009) Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer 101:124–131. doi:10.1038/sj.bjc.6605127

    Article  PubMed  CAS  Google Scholar 

  25. Eoli M, Menghi F, Bruzzone MG, De Simone T, Valletta L, Pollo B, Bissola L, Silvani A, Bianchessi D, D’Incerti L, Filippini G, Broggi G, Boiardi A, Finocchiaro G (2007) 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 13:2606–2613. doi:10.1158/1078-0432.CCR-06-2184

    Article  PubMed  CAS  Google Scholar 

  26. Felsberg J, Rapp M, Loeser S, Fimmers R, Stummer W, Goeppert M, Steiger HJ, Friedensdorf B, Reifenberger G, Sabel MC (2009) Prognostic significance of molecular markers and extent of resection in primary glioblastoma patients. Clin Cancer Res 15:6683–6693. doi:10.1158/1078-0432.CCR-08-2801

    Article  PubMed  CAS  Google Scholar 

  27. Gerstner ER, Yip S, Wang DL, Louis DN, Iafrate AJ, Batchelor TT (2009) MGMT methylation is a prognostic biomarker in elderly patients with newly diagnosed glioblastoma. Neurology 73:1509–1510. doi:10.1212/WNL.0b013e3181bf9907

    Article  PubMed  CAS  Google Scholar 

  28. Glas M, Happold C, Rieger J, Wiewrodt D, Bahr O, Steinbach JP, Wick W, Kortmann R, Reifenberger G, Weller M, Herrlinger U (2009) Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. J Clin Oncol 27:1257–1261. doi:10.1200/JCO.2008.19.2195

    Article  PubMed  CAS  Google Scholar 

  29. Hegi ME, Diserens A, Godard S, Dietrich P, Regli L, Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) 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. doi:10.1158/1078-0432.CCR-03-0384

    Article  PubMed  CAS  Google Scholar 

  30. Kamiryo T, Tada K, Shiraishi S, Shinojima N, Kochi M, Ushio Y (2004) Correlation between promoter hypermethylation of the O6-methylguanine-deoxyribonucleic acid methyltransferase gene and prognosis in patients with high-grade astrocytic tumors treated with surgery, radiotherapy, and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea-based chemotherapy. Neurosurgery 54:349–357; discussion 357

    Article  PubMed  Google Scholar 

  31. Karayan-Tapon L, Quillien V, Guilhot J, Wager M, Fromont G, Saikali S, Etcheverry A, Hamlat A, Loussouarn D, Campion L, Campone M, Vallette FM, Gratas-Rabbia-Re C (2010) Prognostic value of O6-methylguanine-DNA methyltransferase status in glioblastoma patients, assessed by five different methods. J Neurooncol 97:311–322. doi:10.1007/s11060-009-0031-1

    Article  PubMed  CAS  Google Scholar 

  32. Metellus P, Coulibaly B, Nanni I, Fina F, Eudes N, Giorgi R, Barrie M, Chinot O, Fuentes S, Dufour H, Ouafik L, Figarella-Branger D (2009) Prognostic impact of O6-methylguanine-DNA methyltransferase silencing in patients with recurrent glioblastoma multiforme who undergo surgery and carmustine wafer implantation: a prospective patient cohort. Cancer 115:4783–4794. doi:10.1002/cncr.24546

    Article  PubMed  CAS  Google Scholar 

  33. Park CK, Park SH, Lee SH, Kim CY, Kim DW, Paek SH, Kim DG, Heo DS, Kim IH, Jung HW (2009) Methylation status of the MGMT gene promoter fails to predict the clinical outcome of glioblastoma patients treated with ACNU plus cisplatin. Neuropathology 29:443–449. doi:10.1111/j.1440-1789.2008.00998.x

    Article  PubMed  Google Scholar 

  34. Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, Bekele BN, Aldape KD (2010) MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol 12:116–121. doi:10.1093/neuonc/nop020

    PubMed  CAS  Google Scholar 

  35. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO, European Organisation for Research, Treatment of Cancer Brain Tumour, Radiation Oncology Groups, National Cancer Institute of Canada Clinical Trials Group (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 10:459–466. doi:10.1016/S1470-2045(09)70025-7

    Article  PubMed  CAS  Google Scholar 

  36. Watanabe T, Katayama Y, Komine C, Yoshino A, Ogino A, Ohta T, Fukushima T (2005) O6-methylguanine-DNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course. Int J Cancer 113:581–587. doi:10.1002/ijc.20625

    Article  PubMed  CAS  Google Scholar 

  37. Weller M, Felsberg J, Hartmann C, Berger H, Steinbach JP, Schramm J, Westphal M, Schackert G, Simon M, Tonn JC, Heese O, Krex D, Nikkhah G, Pietsch T, Wiestler O, Reifenberger G, von Deimling A, Loeffler M (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 27:5743–5750. doi:10.1200/JCO.2009.23.0805

    Article  PubMed  CAS  Google Scholar 

  38. Esteller M (2006) Epigenetics provides a new generation of oncogenes and tumour-suppressor genes. Br J Cancer 94:179–183. doi:10.1038/sj.bjc.6602918

    Article  PubMed  CAS  Google Scholar 

  39. Pegg AE, Dolan ME, Moschel RC (1995) Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase. Prog Nucleic Acid Res Mol Biol 51:167–223

    Article  PubMed  CAS  Google Scholar 

  40. Bobustuc GC, Baker CH, Limaye A, Jenkins WD, Pearl G, Avgeropoulos NG, Konduri SD (2010) Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro Oncol. doi:10.1093/neuonc/noq044

  41. Quinn JA, Jiang SX, Reardon DA, Desjardins A, Vredenburgh JJ, Rich JN, Gururangan S, Friedman AH, Bigner DD, Sampson JH, McLendon RE, Herndon JE II, Walker A, Friedman HS (2009) Phase II trial of temozolomide plus O6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol 27:1262–1267. doi:10.1200/JCO.2008.18.8417

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. Michael Stoto at the Harvard School of Public Health for his instruction and constructive feedback on this manuscript.

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Authors and Affiliations

  1. Centre for the North, Department of Radiation Oncology, University of British Columbia and British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada

    Robert A. Olson

  2. Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA

    Robert A. Olson, Priscilla K. Brastianos & David A. Palma

  3. Department of Medical Oncology, Harvard Medical School and Dana Farber/Brigham and Women’s Cancer Center, 44 Binney Street, Boston, MA, 02115, USA

    Priscilla K. Brastianos

  4. Department of Hematology and Oncology, Massachusetts General Hospital Cancer Center, 275 Cambridge Street, Boston, MA, 02114, USA

    Priscilla K. Brastianos

  5. Division of Radiation Oncology, University of Western Ontario and London Regional Cancer Program, 790 Commissioners Road East, London, ON, N6A 4L6, Canada

    David A. Palma

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Olson, R.A., Brastianos, P.K. & Palma, D.A. Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis. J Neurooncol 105, 325–335 (2011). https://doi.org/10.1007/s11060-011-0594-5

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