A 55-year-old man with recurrent glioblastoma (GBM) on temozolomide shows disease progression. Tumor testing reveals MGMT promoter methylation. What is the significance of MGMT methylation in GBM?
- A It silences the MGMT gene, reducing O6-methylguanine-DNA repair and predicting better response to alkylating agents ✓
- B It confers resistance to temozolomide by increasing DNA repair
- C It activates the IDH1 mutation leading to production of 2-hydroxyglutarate
- D It identifies secondary GBM arising from lower-grade glioma
Explanation
MGMT (O6-methylguanine-DNA methyltransferase) is a DNA repair enzyme that removes alkyl groups from the O6 position of guanine — the primary lesion caused by temozolomide. When the MGMT promoter is hypermethylated, MGMT expression is silenced, so tumor cells cannot repair temozolomide-induced DNA damage, resulting in significantly better overall survival with combined radiation and temozolomide. MGMT methylation is found in ~45% of GBMs and is the strongest predictive biomarker for alkylating agent benefit. IDH1 mutation is separate and is the hallmark of secondary (lower-grade progressor) GBM.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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Written and medically reviewed by the StethoPrep medical team.