AbstractMethylation 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.5,6

Review of EvidenceOne of the initial papers that showed MGMTmethylation status as an independent prognostic factor

in 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.9

There 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 of

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EVIDENCE BASED NEURO-ONCOLOGY

The significance of MGMT methylation in Glioblastoma Multiforme prognosisAaida Mumtaz Rao, Ayesha Quddusi, Muhammad Shahzad Shamim

Aga Khan University Hospital, Karachi, Pakistan.Correspondence: Muhammad Shahzad Shamim.Email: shahzad.shamim@aku.edu

Figure-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.10

The 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 survival

than male patients.15

ConclusionMGMT 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.

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Figure-2 (a,b): MRI T1WI axial sections with and without contrast of the same patient, showing complete resection of tumor.

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