IDH2

Overview

IDH2 encodes mitochondrial isocitrate dehydrogenase 2; hotspot neomorphic mutations (e.g. R172) produce 2-hydroxyglutarate and drive T follicular helper (TFH)–phenotype lymphomas and AML.

Alterations observed in the corpus

  • Mutated in 11% (15/132) of nodal peripheral T-cell lymphomas profiled on MSK-IMPACT PMID:37078708.
  • IDH1/IDH2 mutation required for inclusion in a 128-patient MSKCC WHO 2016 Grade 2 IDH-mutant low-grade glioma active-surveillance cohort; verified by IHC (93.8%) and/or NGS (57%) PMID:37910594.
  • IDH1 or IDH2 mutation status defines the GCIMP phenotype with high DNA methylation in glioma; IDH-mutant gliomas undergo progressive epigenetic demethylation (674 CpG probes, >15% difference) at recurrence, especially after temozolomide and/or radiotherapy, per the GLASS consortium (132 matched initial and recurrent gliomas) PMID:38117484.
  • IDH1 or IDH2 mutation was confirmed in all 6 grade II oligodendrogliomas by Sanger sequencing and whole-exome sequencing; IDH mutations co-occur with 1p/19q codeletion confirmed by FISH in all six tumors PMID:27806376.
  • IDH2 mutations were identified among recurrent genomic alterations in prostate cancer by integrative genomic profiling PMID:20579941
  • Recurrently mutated in AML; IDH2 mutations co-occur with distinctive CpG methylation patterns; contribute to prognostic stratification of intermediate-risk patients alongside IDH1 and TET2 PMID:23634996
  • No IDH2 mutations detected in the TCGA 2013 primary GBM cohort (n=291 WES/291 tumor-normal pairs); only IDH1 R132H/G/C mutations were observed (6% of cases), emphasizing IDH2 as non-driver in primary adult GBM PMID:24120142
  • Somatic variants in 3 MPN patients combined (with IDH1) in whole-exome sequencing of myeloproliferative neoplasms (ET, PV, MF) as part of the CALR discovery cohort PMID:24325359
  • Codon 172 hotspot missense mutations in intrahepatic cholangiocarcinoma (IHCH); absent in gallbladder carcinoma (GBC) in this study; IDH mutation associated with worse 3-year survival (HR 7.37, P=0.037 adjusted) PMID:24185509
  • Among 60 genes with COSMIC hotspot mutations identified as potential drug targets across non-clear cell RCC subtypes PMID:25401301
  • IDH2 hotspot mutations in 13–29% intrahepatic CCA alongside IDH1; rare in extrahepatic CCA; IDH inhibitor resistance can involve isoform switching from IDH1 to IDH2 PMID:25526346
  • IDH1/IDH2 mutations in iCCA drive 2-HG accumulation, epigenetically suppressing bile acid biosynthesis genes (e.g., CYP7A1) via DNA hypermethylation; ivosidenib (IDH1-specific) is the approved therapy highlighted as first targeted option for IDH1-mutant CCA. PMID:25608663
  • Defining hotspot mutation (alongside IDH1) across LGm1–3 / LGr1–3 IDH-mutant glioma subtypes in pan-glioma TCGA analysis (n=1122); IDH1/2 status forms the primary axis of methylome and transcriptome separation across diffuse glioma subtypes PMID:26824661
  • IDH2 R140 co-occurs strongly with NPM1 (OR 3.6, P=5e-10) while IDH2 R172 is mutually exclusive with NPM1 (OR 0.06, P=4e-5) and forms a provisional AML subgroup (1%, n=18) in a cohort of 1540 adults; DNMT3A × IDH2 R140 co-occurrence (n=19) was adverse (q=0.05) PMID:27276561
  • Covered by both the 264-gene and 8-gene amplicon panels in a 116-patient AML/MDS decitabine trial; previously hypothesized to predict hypomethylating-agent response but not validated as predictive of 10-day decitabine response. PMID:27959731
  • R172K mutation in 1/19 sequenced 1p/19q-codeleted oligodendroglioma cases; wild-type in 1p/19q-intact glioblastoma-like cases; OncoKB Level 3B PMID:28472509
  • Enriched in cholangiocarcinoma Cluster 4 alongside IDH1 (31.6% vs 1.0% in other clusters, q < 0.001); proposed driver of CpG-shore DNA hypermethylation via 2-hydroxyglutarate oncometabolite production PMID:28667006

Cancer types (linked)

  • PTCL / AITL — 11% frequency in the MSK cohort PMID:37078708.
  • ODG — IDH2 mutation confirmed in oligodendrogliomas; co-occurs with 1p/19q codeletion in all six cases studied PMID:27806376.

Co-occurrence and mutual exclusivity

  • Part of the TET2/DNMT3A/RHOA/IDH2 TFH-phenotype driver landscape in nodal PTCL PMID:37078708.

Therapeutic relevance

  • No independent prognostic effect reported for IDH2 in CHOP-treated PTCL in this cohort PMID:37078708.

Open questions

  • None flagged in the corpus.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:20579941

This page was processed by crosslinker on 2026-05-14. - PMID:23634996

This page was processed by crosslinker on 2026-05-14. - PMID:24120142

This page was processed by crosslinker on 2026-05-14. - PMID:24325359

This page was processed by crosslinker on 2026-05-14. - PMID:24185509

This page was processed by crosslinker on 2026-05-14. - PMID:25401301

This page was processed by crosslinker on 2026-05-14. - PMID:25526346

This page was processed by crosslinker on 2026-05-14. - PMID:25608663

This page was processed by crosslinker on 2026-05-14. - PMID:26824661

This page was processed by entity-page-writer on 2026-05-15. - PMID:27276561

This page was processed by entity-page-writer on 2026-05-15. - PMID:27959731

This page was processed by entity-page-writer on 2026-05-15. - PMID:28472509

This page was processed by entity-page-writer on 2026-05-15. - PMID:28667006

This page was processed by wiki-cli on 2026-05-15.