Neurosurgery notes/Tumours/Tumour genetics/Glioma pathology/MGMT methylation

MGMT methylation

View Details
Status
Done
logo
Parent item
Glioma pathology

General

  • Naturally occurs on chromosome 10q26 of the DNA
  • Occurs in 45-75% of glioblastomas.
    • Reduced levels of MGMT activity

Mechanism

  • MGMT is a DNA repair enzyme that can remove the methyl group placed by temozolomide, thereby negating the cytotoxic effects of temozolomide.
    • Therefore, patients who express low levels of MGMT respond better to temozolomide

Clinical significance

LGG

  • Baumert 2016 EORTC III
    • All IDHmt/codel and 90% of the IDHmt/non-codel tumors have a methylated MGMT promoter → MGMT testing does not provide additional prognostic or predictive value in the IDHmt subgroup
    • IDHwt tumors, MGMT may be of a predictive value

Glioblastoma

  • Stupp et al., 2005 and Stupp 2009 → For GBM
      • ㅤ
      Deaths/pt
      Hazard ration (95% CI)
      Median (months, 95% CI)
      2 year (%)
      3 year (%)
      4 year (%)
      5 year (%)
      MGMT unmethylated
      ㅤ
      ㅤ
      ㅤ
      ㅤ
      ㅤ
      ㅤ
      ㅤ
      Radiotherapy
      54/54
      1·0
      11·8 (10·0–14·4)
      1·8 (0·1–8·6)
      0
      0
      0
      Combined
      54/60
      0·6 (0·4–0·8)
      12·6 (11·6–14·4)
      14·8 (7·2–25·0)
      11.1 (4.7-20.7)
      11.1 (4.7-20.7)
      8·3 (2·7–18·0)
      MGMT methylated*
      ㅤ
      ㅤ
      ㅤ
      ㅤ
      ㅤ
      ㅤ
      ㅤ
      Radiotherapy
      43/46
      0·5 (0·3–0·7)
      15·3 (13·0–20·9)
      23·9 (12·9–36·9)
      7·8 (2·2–18·3)
      7·8 (2·2–18·3)
      5.2 (1.0-15.0)
      Combined
      37/46
      0·3 (0·2–0·4)
      23·4 (18·6–32·8)
      48·9 (33·7–62·4)
      27·6 (15·4–41·4)
      22.1 (11.0-35.7)
      13.8 (4.5-28.2)
      Kaplan-Meier overall survival including subgroup analyses
    • Data are percentage survival (95% CI) unless otherwise stated. *HR relative to radiotherapy unmethylated.
    • The MGMT status was found to be the single most important predictive factor for a favourable outcome.
    • MGMT methylation status (Strupp 2009)
      • MGMT methylated
        • Median survival: 19.3 months
      • MGMT non methylated
        • Median survival: 12.0 months
  • Weller et al., 2015
    • Recent data suggests that MGMT methylation is a prognostic biomarker for dose- intense temozolomide rechallenge