Frequent MGMT (06-methylguanine-DNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience
Background. The aim of this retrospective study was to analyse the MGMT (06-methylguanine-DNA methyltransferase) promoter methylation status in long-term surviving (≥ 3 years) patients with glioblastoma multiforme (GBM).
Methods. The methylation status of the MGMT promoter was determined by bisulfite modification of the DNA and subsequent methylation-specific polymerase-chain-reaction (MSP). DNA was extracted from routinely formalin-fixed and paraffin-embedded tumour tissue samples.
Results. MSP yielded interpretable results in only 14 of 33 (42%) long-term surviving patients with GBM. A methylated band was seen in 3 of 14, methylated as well as unmethylated bands in 8 of 14 and an only unmethylated band in 3 of 14 patients, thus, yielding MGMT promoter methylation in 11 of 14 patients. The two groups of patients with methylated and unmethylated MGMT promoter status were too small to draw any firm statistical conclusions.
Conclusions. Long-term surviving patients with GBM have very frequently intratumoural MGMT promoter methylation. This phenomenon discriminates long-term survivors from a non-selected group of patients with GBM. The standardization of the MSP for the determination of the MGMT promoter methylation status seems to be necessary in order to make this methodology a more reliable one.
Velnar T, Smrdel U, Popovic M, Bunc G. Genetic markers in oligodendroglial tumours. Radiol Oncol 2010; 44: 13-18.
Kachanov DY, 2, Dobrenkov KV, Shamanskaya TV, 2, Abdullaev RT, 2, Inushkina EV, Savkova RF, et al. Solid tumors in young children in Moscow Region of Russian Federation. Radiol Oncol 2008; 42: 39-44.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: 459-66.
Martinez R, Schackert G, Esteller M. Hypermethylation of the proapoptotic gene TMS1/ASC: prognostic importance in glioblastoma multiforme. J Neurooncol 2007; 82: 133-9.
Burton EC, Lamborn KR, Forsyth P, Scott J, O'Campo J, Uyehara-Lock J, et al. Aberrant p53, mdm2, and proliferation differ in glioblastomas from long-term compared with typical survivors. Clin Cancer Res 2002; 8: 180-7.
Steinbach JP, Blaicher HP, Herrlinger U, Wick W, Nägele T, Meyermann R, et al. Surviving glioblastoma for more than 5 years: The patient's perspective. Neurology 2006; 66: 239-42.
Burton EC, Lamborn KR, Feuerstein BG, Prados M, Scott J, Forsyth P, et al. Genetic aberrations defined by comparative genomic hybridization distinguish long-term from typical survivors of glioblastoma. Cancer Res 2002; 62: 6205-10.
McLendon RE and Halperin EC. Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Cancer 2003; 98: 1745-8.
Senger D, Cairncross JG, Forsyth PAJ. Long-term survivors of glioblastoma: statistical aberration or important unrecognized molecular subtype? Cancer J 2003; 9: 214-21.
Scott JN, Rewcastle NB, Brasher PMA, Fulton D, MacKinnon JA, Hamilton M, et al. Which glioblastoma multiforme patient will become a long-term survivor? A population-based study. Ann Neurol 1999; 46: 183-8.
Vertosick FT, Selker RG. Long-term survival after the diagnosis of malignant glioma. A series of 22 patients surviving more than 4 years after diagnosis. Surg Neurol 1992; 38: 359-63.
Salvati M, Cervoni L, Artico M, Caruso R, Gagliardi FM. Long-term survival in patients with supratentorial glioblastoma. J Neurooncol 1998; 36: 61-4.
Morita M, Rosenblum MK, Bilsky MH, Fraser RAR, Rosenfeld MR. Long-term survivors of glioblastoma multiforme: clinical and molecular characteristics. J Neurooncol 1996; 27: 259-66.
Nieder C, Grosu AL, Astner S, Molls M. Treatment of unresectable glioblastoma multiforme. Anticancer Res 2005; 25: 4605-10.
Gorlia T, van den Bent MJ, Hegi ME, Mirimanoff RO, Weller M, Cairncross JG, et al. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol 2008; 9: 29-38.
Scott CB, Scarantino C, Urtasun R, Movsas B, Jones CU, Simpson JR, et al. Validation and predictive power of radiation therapy oncology group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06. Int J Rad Oncol Biol Phys 1998; 40: 51-5.
Vranic A. Antigen expression on recurrent meningioma cells. Radiol Oncol 2010; 44: 107-12.
Martinez R, Schackert G, Yaya-Tur R, Rojas-Marcos I, Herman JG, Esteller M. Frequent hypermethylation of the DNA repair gene MGMT in long-term survivors of glioblastoma multiforme. J Neurooncol 2007; 83: 91-3.
Hau P, Stupp R, Hegi ME. MGMT methylation status: the advent of stratified therapy in glioblastoma? Dis Markers 2007; 23: 97-104.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. New Engl J Med 2005; 352: 997-1003.
Glas M, Happold C, Rieger J, Wiewrodt D, Bähr O, Steinbach JP, et al. Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. J Clin Oncol 2009; 27: 1257-61
Sonoda Y, Kumabe T, Watanabe M, Nakazato Y, Inoue T, Kanamori M, et al. Long-term survivors of glioblastoma: clinical features and molecular analysis. Acta Neurochir (Wien) 2009; 151: 1349-58.
Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, et al. Long-term survival with glioblastoma multiforme. Brain 2007; 130: 2596-606.
Balana C, Ramirez JL, Taron M, Roussos Y, Ariza A, Ballester R, et al. O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolomide plus cisplatin in glioblastoma multiforme. Clin Cancer Res 2003; 9: 1461-8.
Kamiryo T, Tada K, Shiraishi S, Shinojima N, Kochi M, Ushio Y. 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 2004; 54: 349-57.
Blanc JL, Wager M, Guilhot J, Kusy S, Bataille B, Chantereau T, et al. Correlation of clinical features and methylation status of MGMT gene promoter in glioblastomas. J Neurooncol 2004; 68: 275-83.
Weaver KD, Grossman SA, Herman JG. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma. Cancer Invest 2006; 24: 35-40.
Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000; 343: 1350-4.
Brandes AA, Tosoni A, Cavallo G, Bertorelle R, Gioia V, Franceschi E, 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 neurooncologia (GICNO). Br J Cancer 2006; 95: 1155-60.
Hassler M, Seidl S, Fazeny-Doerner B, Preusser M, Hainfellner J, Rössler K, et al. Diversity of cytogenetic and pathohistologic profiles in glioblastoma. Cancer Genet Cytogenet 2006; 166: 46-55.
Criniere E, Kaloshi G, Laigle-Donadey F, Lejeune J, Auger N, Benouaich-Amiel A, et al. MGMT prognostic impact on glioblastoma is dependent on therapeutic modalities. J Neurooncol 2007; 83: 173-9.
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 2004; 10: 1871-4.
Herrlinger U, Rieger J, Koch D, Loeser S, Blaschke B, Kortmann RD, et al. Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03. J Clin Oncol 2006; 24: 4412-7.
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. Labor Invest 2007; 87: 392-7.
Aldape KD, Jones G, Wang M, Hegi M, Janzer RC, Stupp R, et al. MGMT methylation testing in RTOG 0525: A phase III trial of newly diagnosed glioblastoma [abstract]. J Clin Oncol 2009; 27(Suppl), 15S. No. 2051.
Dehdashti AR, Hegi ME, Regli L, Pica A, Stupp R. New trends in the medical management of glioblastoma multiforme: the role of temozolomide chemotherapy. Neurosurg Focus 2006; 20: 1-6.
Gonzalez-Gomez P, Bello MJ, Arjona D, Lomas J, Alonso ME, De Campos JM, et al. Promoter hypermethylation of multiple genes in astrocytic gliomas. Int J Oncol 2003; 22: 601-8.
Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W, et al. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 2010; 6: 39-51.
Preusser M, Elezi L, Hainfellner JA. Poor reliability and reproducibility of PCR-based testing of O6-methylguanine-DNA methyltransferase gene (MGMT) promoter methylation status in formalin-fixed and paraffin-embedded neurosurgical biopsy specimens. Clin Neuropathol 2008; 27: 388-90.
Ho DM, Hsu CY, Ting LT, Chiang H. MIB-1 and DNA Topoisomerase IIα could be helpful for predicting long-term survival of patients with glioblastoma. Am J Clin Pathol 2003; 119: 715-22.
Deb P, Sharma MC, Mahapatra AK, Agarwal D, Sarkar C. Glioblastoma multiforme with long-term survival. Neurol India 2005; 53: 329-32.
Hottinger AF, Yoon H, DeAngelis LM, Abrey LE. Neurological outcome of long-term glioblastoma survivors. J Neurooncol 2009; 95: 301-5.
Gojkovic Horvat A, Kovac V, Strojan P. Radiotherapy in palliative treatment of painful bone metastases. Radiol Oncol 2009; 43: 213-24.
Pope WB, Sayre J, Perlina A, Villablanca JP, Mischel PS, Cloughesy TF. MR imaging correlates of survival in patients with high-grade gliomas. Am J Neuroradiol 2005; 26: 2466-74.
Hammoud MA, Sawaya R, Shi W, Thall PF, Leeds NE. Prognostic significance of preoperative MRI scans in glioblastoma multiforme. J Neurooncol 1996; 27: 65-73.