Which epigenetic mechanism is specifically exploited by IDH1/IDH2 mutant gliomas and cholangiocarcinomas to drive carcinogenesis via production of an oncometabolite?

• A Fumarate accumulation inhibits succinate dehydrogenase leading to HIF-1alpha stabilization
• B D-2-hydroxyglutarate competitively inhibits alpha-ketoglutarate-dependent dioxygenases including TET2 and histone demethylases, causing a CpG island methylator phenotype (CIMP) ✓
• C L-2-hydroxyglutarate activates mTORC1 signalling cascade, driving cell proliferation
• D Isocitrate accumulation prevents NADPH production, increasing oxidative stress and mutagenesis

Explanation

Mutant IDH1/2 catalyze conversion of alpha-ketoglutarate to D-2-hydroxyglutarate (D-2-HG), the oncometabolite. D-2-HG competitively inhibits alpha-KG-dependent dioxygenases, particularly TET2 (DNA demethylase) and KDM histone demethylases, resulting in genome-wide DNA hypermethylation (CpG island methylator phenotype, CIMP) and altered histone methylation. This epigenetic silencing of tumor suppressor genes drives malignant transformation. Fumarate accumulation is the mechanism in SDH-deficient tumors (paraganglioma, HLRCC), not IDH mutations. L-2-HG is produced by mutant LDH in certain contexts. Isocitrate accumulation is not the oncometabolic mechanism.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.