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CNS: MGMT and IDH significance

Free question published 04 August 2026

Central nervous systemMGMT and IDH significance

A 62-year-old woman with newly diagnosed glioblastoma, IDH-wildtype, is being counselled about the value of MGMT promoter methylation testing on her tumour specimen. She asks specifically what the methylation result tells her about whether temozolomide will help. Which statement best describes the role of MGMT promoter methylation?

  1. AIt is a purely prognostic marker that does not predict benefit from any specific treatment
  2. BMethylation of the MGMT promoter predicts benefit from temozolomide, whereas unmethylated tumours derive little benefit
  3. CUnmethylated MGMT predicts greater temozolomide benefit because the repair enzyme is absent
  4. DMGMT methylation predicts benefit from PCV chemotherapy rather than temozolomide
  5. EMGMT methylation is only relevant in 1p/19q-codeleted tumours

Why B is correct

Hegi et al (NEJM 2005), the molecular analysis of the Stupp EORTC-NCIC cohort, showed that patients whose tumour had a methylated MGMT promoter benefited from temozolomide (median survival 21.7 versus 15.3 months) while unmethylated tumours derived little benefit. Methylation silences the MGMT DNA-repair enzyme, so the alkylator damage induced by temozolomide is not reversed. MGMT methylation is therefore both prognostic and predictive of temozolomide benefit.

And why the others are not

  • AIncorrect: MGMT methylation is predictive, not merely prognostic, in the Hegi analysis.
  • CIncorrect: this reverses the biology; methylation silences the repair enzyme, so methylated tumours are more sensitive to temozolomide.
  • DIncorrect: the predictive relationship demonstrated was with temozolomide, not PCV.
  • EIncorrect: MGMT methylation testing is relevant across high-grade gliomas and is recommended on all such specimens; it is not confined to codeleted tumours.

Source Hegi — MGMT gene silencing and benefit from temozolomide in glioblastoma — Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003.

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