Methylation of O6-methylguanine-DNA methyltransferase (MGMT) has been extensively studied as a biomarker in predicting the prognosis of patients with GBM (Glioblastoma multiforme). Its significance has been studied in various subgroups, including age, gender and even race. Correlation between prognosis with MGMT methylation and different treatment regimens has also been studied in detail. There are multiple techniques to analyze MGMT methylation in tumour specimen. We review the current evidence for the importance of MGMT methylation as a biomarker for prognosis in GBM patients, the techniques to analyze it and the effect of epidemiologic factors on its significance

Quddusi, Ayesha

Rao, Aaida Mumtaz

Shamim, Muhammad Shahzad

English

eCommons@AKU

eCommons@AKUSection of Neurosurgery Department of SurgeryJuly 2018The significance of MGMT methylation inglioblastoma multiforme prognosisAaida Mumtaz RaoAga Khan UniversityAyesha QuddusiAga Khan University, ayeshaquddusi@hotmail.comMuhammad Shahzad ShamimAga Khan University, shahzad.shamim@aku.eduFollow this and additional works at: https://ecommons.aku.edu/pakistan_fhs_mc_surg_neurosurgRecommended CitationRao, A., Quddusi, A., Shamim, M. (2018). The significance of MGMT methylation in glioblastoma multiforme prognosis. Journal ofPakistan Medical Association, 68(7), 1137-1139.Available at: https://ecommons.aku.edu/pakistan_fhs_mc_surg_neurosurg/157AbstractMethylation of O6-methylguanine-DNAmethyltransferase (MGMT) has beenextensively studied as a biomarker inpredicting the prognosis of patients with GBM(Glioblastoma multiforme). Its significance hasbeen studied in various subgroups, includingage, gender and even race. Correlationbetween prognosis with MGMT methylationand different treatment regimens has alsobeen studied in detail. There are multipletechniques to analyze MGMT methylation intumour specimen. We review the currentevidence for the importance of MGMTmethylation as a biomarker for prognosis inGBM patients, the techniques to analyze it andthe effect of epidemiologic factors on itssignificance.Keywords: Glioblastoma multiforme, tumourmarkers, MGMT methylation.BackgroundGlioblastoma is the most common primary brain tumourin adults. The standard treatment includes surgicalresection, radiotherapy (RT) and chemotherapy, mostlywith alkylating agent Temozolamide (TMZ). Despitethese regimens, prognosis remains poor.1 Variousbiomarkers are used to predict prognosis of patients withGBM.2 Amongst these, methylation of O6-methylguanine-DNA methyltransferase (MGMT) isconsidered to be a biomarker for good prognosis.3,4MGMT is a DNA repair protein, that repairs damage fromalkylating agents. Methylation of MGMT gene can silenceits expression, leading to cell death after damage fromalkylating agents that can facilitate cell death of cancercells in GBM.5,6Review of EvidenceOne of the initial papers that showed MGMTmethylation status as an independent prognostic factorin GBM patients was by Hegi et al. They demonstratedthat MGMT methylation was associated with betteroverall survival in GBM patients treated with TMZ plusRT as well as patients receiving RT alone.7 A recentmeta-analysis of 34 clinical trials concluded that MGMTmethylation was significantly associated with betteroverall survival (OS) in patients with GBM.3 This is trueeven for tumours that are not suitable for resection.4For recurrent GBM also not suitable for resection, aretrospective study by Kim et al., showed correlation ofMGMT promoter methylation status with betterprogression free survival (PFS), and OS in patients whounderwent gamma knife radiosurgery.8 MGMTmethylation, and low MGMT expression were alsoidentified as favourable prognostic markers in patientswith newly diagnosed GBM, who underwentimplantation of carmustine releasing wafers (Gliadel)after surgery.9There are several different techniques available toanalyze MGMT methylation status in GBM tumours.Christians et al., compared the use of methylationspecific polymerase chain reaction (MSP), methylationspecific multiplex ligation-dependent probeamplification (MS-MLPA) and pyrosequencing inmethylation analysis of MGMT, and found thatpyrosequencing was the most useful tool in analysis ofVol. 68, No. 7, July 20181137EVIDENCE BASED NEURO-ONCOLOGYThe significance of MGMT methylation in Glioblastoma Multiforme prognosisAaida Mumtaz Rao, Ayesha Quddusi, Muhammad Shahzad ShamimAga Khan University Hospital, Karachi, Pakistan.Correspondence: Muhammad Shahzad Shamim.Email: shahzad.shamim@aku.eduFigure-1 (a,b): MRI T1WI axial sections with and without contrast, showing a large GBM in right occipitalregion.MGMT methylation status in terms of predicting clinicaloutcome and cost effectiveness when a large number ofsamples have to be analyzed. However, MSP was usefulfor routine clinical diagnostics with a smaller number ofsamples.10The status of MGMT methylation as a predictivebiomarker in prognosis may be effected by age,gender, and race. It is an important prognostic factorfor OS, as well as PFS in elderly patients treated withTMZ and RT.11 In paediatric GBM studies, MGMTmethylation has also been observed as a predictor ofincreased PFS, however these studies have a smallsample size. Rizzo et al., showed that the presence ofMGMT methylation in paediatric population is rare.12The importance of MGMT methylation also differs byarea and continents. A recent systematic review andmeta-analysis noted that while MGMT methylationremained a significant marker of PFS in patients indifferent parts of the world, it did not hold the samesignificance regarding OS in Asian patients withMGMT methylation compared to patients in US andEurope.13 Similarly, in another systematic review andmeta-analysis MGMT promoter methylation hadsignificant effect on OS in Asian population but noton PFS, while it had a significant effect on both OSand PFS in Caucasian population.14 Gender alsoappears to have an impact on the importance ofMGMT methylation in predicting prognosis. In arecent study, Franceschi et al., observed that femalepatients with MGMT methylation had longer survivalthan male patients.15ConclusionMGMT methylation has beenshown to be significantlyassociated with PFS and OS inGBM patients and can be used asa prognostic marker. There areseveral ways to assess it and MSPas well as pyrosequencingappear to be good techniques toanalyze MGMT methylationstatus. However, GBM biology iscomplex and MGMT methylationis not the only prognosticbiomarker. The current evidencesuggests that epidemiologicfactors such as age, gender andrace also appear to affect itsimportance as a marker.However, there are too fewstudies to establish a link here.References1. Waqas M, Khan I, Shamim MS. Role of 5-ALA in improving extentof tumor resection in patients with glioblastoma multiforme. J PakMed Assoc 2017; 67: 1630-2.2. Khan I, Waqas M, Shamim MS. Prognostic significance of IDH 1mutation in patients with glioblastoma multiforme. J Pak MedAssoc 2017; 67: 816-7.3. Binabaj MM, Bahrami A, ShahidSales S, Joodi M, Joudi Mashhad M,Hassanian SM, et al. The prognostic value of MGMT promotermethylation in glioblastoma: A meta-analysis of clinical trials. JCell Physiol 2018; 233: 378-86.4. 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. JNeurolNeurosurg Psychiatry 2011; 82: 441.5. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG.Inactivation of the DNA repair gene O6-methylguanine-DNAmethyltransferase by promoter hypermethylation is a commonevent in primary human neoplasia. Cancer Research 1999; 59:793-7.6. Bobola MS, Berger MS, Silber JR. Contribution of O6-methylguanine-DNA methyltransferase to resistance to 1, 3-(2-chloroethyl)-1-nitrosourea in human brain tumor-derived celllines. Molecular Carcinogenesis 1995; 13: 81-8.7. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M,et al. MGMT gene silencing and benefit from temozolomide inglioblastoma. N Engl J Med 2005; 352: 997-1003.8. Kim BS, Kong DS, Seol HJ, Nam DH, Lee JI. MGMT promotermethylation status as a prognostic factor for the outcome ofgamma knife radiosurgery for recurrent glioblastoma. Journal ofNeuro-Oncology 2017; 133: 615-22.9. Lechapt-Zalcman E, Levallet G, Dugué AE, Vital A, Diebold M-D, Menei P, et al. O(6) -methylguanine-DNA methyltransferase(MGMT) promoter methylation and low MGMT-encodedprotein expression as prognostic markers in glioblastomapatients treated with biodegradable carmustine waferimplants after initial surgery followed by radiotherapy withJ Pak Med Assoc1138 A. M. Rao, A. Quddusi, M. S. ShamimFigure-2 (a,b): MRI T1WI axial sections with and without contrast of the same patient, showing complete resection of tumor.concomitant and adjuvant temozolomide. Cancer 2012; 118:4545-54.10. Christians A, Hartmann C, Benner A, Meyer J, von Deimling A,Weller M, et al. Prognostic value of three different methods ofMGMT promoter methylation analysis in a prospective trial onnewly diagnosed glioblastoma. PLoS ONE 2012; 7: e33449.11. Minniti G, Salvati M, Arcella A, Buttarelli F, D'Elia A, Lanzetta G, etal. Correlation between O6-methylguanine-DNAmethyltransferase and survival in elderly patients withglioblastoma treated with radiotherapy plus concomitant andadjuvant temozolomide. J Neurooncol 2011; 102: 311-6.12. Rizzo D, Ruggiero A, Martini M, Rizzo V, Maurizi P, Riccardi R.Molecular biology in pediatric high-grade glioma: Impact onprognosis and treatment. Biomed Res Int 2015; 2015: 215135. doi:10.1155/2015/215135.13. Meng W, Jiang Y, Ma J. Is the prognostic significance of O6-methylguanine- DNA methyltransferase promoter methylationequally important in glioblastomas of patients from differentcontinents? A systematic review with meta-analysis. CancerManag Res 2017; 9: 411-25.14. Yang H, Wei D, Yang K, Tang W, Luo Y, Zhang J. The prognosis ofMGMT promoter methylation in glioblastoma patients of differentrace: a meta-analysis. Neurochem Res 2014; 39: 2277-87.15. Franceschi E, Tosoni A, Minichillo S, Depenni R, Paccapelo A,Bartolini S, et al. The prognostic role of gender and MGMTmethylation status in glioblastoma patients: the female power.World Neurosurg 2018; April 112:e342-e347. doi:10.1016/j.wneu.2018.01.045.Vol. 68, No. 7, July 2018The significance of MGMT methylation in Glioblastoma Multiforme prognosis 1139

The significance of MGMT methylation in glioblastoma multiforme prognosis

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The significance of MGMT methylation in glioblastoma multiforme prognosis

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