A 40-year-old patient with IDH-mutant glioblastoma has better prognosis than IDH-wildtype GBM. IDH1/2 mutations produce which oncometabolite that drives epigenetic changes?
- A Succinate, inhibiting prolyl hydroxylases and stabilising HIF-1alpha
- B Fumarate, inhibiting histone demethylases via competitive inhibition
- C 2-hydroxyglutarate (2-HG), a competitive inhibitor of alpha-KG-dependent dioxygenases ✓
- D Lactate, acting as a histone deacetylase inhibitor
Explanation
Mutant IDH1/2 (most commonly IDH1 R132H) acquires neomorphic activity, converting alpha-ketoglutarate (alpha-KG) to 2-hydroxyglutarate (2-HG) rather than isocitrate. 2-HG competitively inhibits alpha-KG-dependent dioxygenases, including TET2 DNA demethylases and Jumonji histone demethylases, leading to global DNA hypermethylation (CpG island methylator phenotype, CIMP) and aberrant histone methylation. This epigenetic reprogramming drives gliomagenesis and partly explains why IDH-mutant gliomas (now classified as astrocytoma, IDH-mutant or oligodendroglioma) are less aggressive. Succinate and fumarate accumulation occurs in SDH/FH-mutant tumours (pheochromocytoma, paraganglioma, renal carcinoma).
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.