IDH1/IDH2 mutations in diffuse gliomas lead to accumulation of which oncometabolite that causes epigenetic dysregulation?
- A 2-hydroxyglutarate (2-HG) ✓
- B Succinate
- C Fumarate
- D Alpha-ketoglutarate
Correct answer: A. 2-hydroxyglutarate (2-HG)
Explanation
Mutant IDH1/2 gains a neomorphic function, converting alpha-ketoglutarate to 2-hydroxyglutarate (2-HG). 2-HG competitively inhibits alpha-KG-dependent dioxygenases, including TET2 DNA demethylases and histone demethylases, causing a hypermethylator phenotype (CpG island methylator phenotype, CIMP). This epigenetic reprogramming blocks cellular differentiation and drives gliomagenesis. IDH-mutant gliomas have better prognosis than IDH-wildtype.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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