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MGMT Methylation – TMZ Predictive Biomarker — SCE Neurology MCQ

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ModerateNeuro-oncologyMGMT Methylation – TMZ Predictive BiomarkerSCE Neurology

A 55-year-old man with a right frontal glioblastoma undergoes the Stupp protocol — maximal safe resection followed by concurrent temozolomide and radiotherapy, then 6 cycles of adjuvant temozolomide. His tumour is MGMT promoter methylated. What is the significance of MGMT methylation?

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Correct answer: D — MGMT promoter methylation predicts better response to temozolomide — methylation silences the MGMT gene (a DNA repair enzyme), preventing repair of temozolomide-induced DNA damage, leading to greater tumour cell death

MGMT (O6-methylguanine-DNA methyltransferase) is a DNA repair enzyme that removes alkyl groups from DNA, counteracting the cytotoxic effect of temozolomide. When the MGMT promoter is methylated (epigenetically silenced), MGMT protein is not produced, so temozolomide-induced DNA damage is not repaired — increasing tumour sensitivity to chemotherapy. Methylated MGMT GBM patients have median survival ~22 months vs ~15 months for unmethylated. A: Major prognostic and predictive significance. C: Still malignant (grade 4). D: Methylation predicts BETTER response. E: Does not predict radiation resistance.

Reference: NICE NG99; Stupp Protocol; Hegi et al. MGMT (NEJM 2005)