IDH1

Overview

IDH1 encodes cytosolic isocitrate dehydrogenase 1; neomorphic hotspot mutations (R132) generate 2-hydroxyglutarate and define a major molecular subgroup of low-grade gliomas and a subset of cholangiocarcinomas.

Alterations observed in the corpus

  • IDH1 (or IDH2) mutation was 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 is an actionable driver in intrahepatic cholangiocarcinoma; the MSK hidden-genome classifier predicted overall survival in IHC independently of IDH1 alteration status PMID:38864854.
  • IDH1 p.R132H was detected in CSF ctDNA from IDH-mutant glioma patients in the csf_msk_2024 cohort (1,007 CSF samples, 711 patients) profiled by MSK-IMPACT PMID:39289779.
  • IDH1 (or IDH2) mutation status determines the epigenetic trajectory of glioma at recurrence: IDH-mutant gliomas (n=72 from the GLASS consortium) show genome-wide progressive DNA hypomethylation (674 CpG probes with >15% difference), while IDH-wildtype gliomas (n=60) have a stable epigenome; treatment with temozolomide and/or radiotherapy accelerates GCIMP-high to GCIMP-low transition (34% vs 4% without treatment, Fisher P=0.005) PMID:38117484.
  • IDH1 or IDH2 mutation was confirmed in all 6 grade II oligodendrogliomas studied by single-cell RNA-seq (Smart-seq2, 4,347 cells); IDH1 point mutations were directly detected in scRNA-seq reads by single-base Bowtie alignment, allowing genotype assignment at single-cell resolution PMID:27806376.
  • IDH1 mutations referenced as a characteristic of cholangiocarcinoma (not GBC) for comparison context in GBC genomic landscape study PMID:36228155
  • Fusion events observed in TNBC WGS cohort (BCCRC, 65 tumors) PMID:22495314
  • Somatic mutations detected in melanoma WES cohort (Broad, 121 tumors) PMID:22817889
  • Recurrently mutated in AML; mutant IDH1 samples show distinctive CpG methylation gains versus normal CD34+CD38− cells; IDH1/IDH2 mutations add prognostic value for intermediate-risk patients beyond current classification schemes PMID:23634996
  • IDH1 R132H hotspot mutation observed in 1 ACC tumor (catalytic-domain hotspot) PMID:23685749
  • R132H/G/C mutations in 6% (28/423 with adequate coverage) of primary GBM (TCGA 2013); concurrent with TP53 in 12/13 cases and ATRX in many; all IDH1-mutant cases were G-CIMP+; no IDH2 mutations detected in the cohort PMID:24120142
  • Somatic variants in 3 MPN patients combined (with IDH2); IDH1 co-mutated with SRSF2 in whole-exome sequencing of myeloproliferative neoplasms (ET, PV, MF) PMID:24325359
  • Codon 132 hotspot missense mutations in intrahepatic cholangiocarcinoma (IHCH); part of the combined 20% IDH mutation rate; IDH mutation associated with significantly worse 3-year survival (33% vs 81%, HR 7.37, P=0.037 adjusted) in a Johns Hopkins/Verona cohort PMID:24185509
  • IDH1 R132H present in every initial tumor and every patient-matched recurrence in a cohort of 23 low-grade glioma patients; the only universally shared mutation across all tumors and recurrences, reinforcing IDH1 as the initiating event in low-grade gliomagenesis; supports mutant-IDH1-directed therapy as a recurrence-spanning strategy PMID:24336570
  • IDH1 hotspot mutations in 13–29% intrahepatic CCA (iCCA), rare in extrahepatic CCA; IDH1-mutant iCCA benefits from ivosidenib (ClarIDHy phase III: mPFS 6.9 vs. 2.7 months, mOS 10.3 vs. 7.5 months) PMID:25526346
  • IDH1 gain-of-function mutations (R132 hotspot) are frequent in iCCA; 2-HG accumulation epigenetically suppresses bile acid biosynthesis genes including CYP7A1, and ivosidenib was approved for IDH1-mutant CCA based on the ClarIDHy phase III PFS benefit. PMID:25608663
  • IDH1 R132 UV hot-spot mutation in ~6% of cutaneous melanomas; enriched in the CIMP epigenetic cluster (OR = 4.05, p = 0.005) in the TCGA 333-sample cohort PMID:26091043
  • R132C hotspot in 1 desmoplastic melanoma tumor; authors identify IDH1 as potentially targetable PMID:26343386
  • R132 hotspot mutations in ~1% of primary prostate cancers define a CIMP-like, ETS-negative, SPOP-wt, SCNA-quiet subtype with genome-wide hypermethylation exceeding that of IDH1-mutant GBM and AML; associated with younger age at diagnosis PMID:26544944
  • Essentially absent (single hotspot only) in this extrahepatic cholangiocarcinoma / periampullary cohort (n=160 AMPAC/DUOAC/CAC), in contrast to intrahepatic CAC where IDH1 mutations are common; underscores molecular distinction between intra- and extrahepatic biliary tumors PMID:26804919
  • Defining hotspot mutation in IDH-mutant glioma macro-cluster (LGm1–3 / LGr1–3 subtypes); 457 IDH1 mutations recovered in pan-glioma TCGA cohort (n=1122), comprising 99% of the IDH-mutant cluster; primary axis of methylome and transcriptome separation between glioma subtypes PMID:26824661
  • IDH1 acts as an early/founding driver in the epigenetic axis in AML; co-mutates with NPM1; among the 5234 driver mutations across 76 genes identified in 1540 AML patients enrolled in German-Austrian AMLSG intensive-therapy trials PMID:27276561
  • Covered by both the 264-gene and 8-gene amplicon panels in a 116-patient AML/MDS trial; previously hypothesized to predict hypomethylating-agent response but not validated as predictive of 10-day decitabine response in this study. PMID:27959731
  • IDH1 R132C identified in pediatric AML as an IDH-inhibitor target; the same variant was separately diagnostic of Maffucci syndrome PMID:28007021.
  • IDH1 R132C identified in a single pheochromocytoma/paraganglioma tumor in a comprehensive multi-platform genomic characterization study PMID:28162975.
  • R132H mutation observed in 13/19 sequenced tumors (68%) in 1p/19q-codeleted oligodendroglioma; absent in 1p/19q-intact glioblastoma-like tumors; OncoKB Level 3B PMID:28472509
  • IDH1 identified as a lineage-restricted driver in glioma; contrasted with pan-cancer drivers TP53 and PIK3CA across a 62-tumor-type pan-cancer sequencing cohort PMID:28481359
  • Enriched in cholangiocarcinoma Cluster 4 (31.6% vs 1.0% in other clusters, q < 0.001); proposed driver of CpG-shore DNA hypermethylation via 2-hydroxyglutarate oncometabolite production; candidate for IDH inhibitors (e.g. ivosidenib) PMID:28667006
  • R132C mutation in 6 medulloblastoma cases (5 SHH, 1 WNT); IDH1-mutant SHH tumours are CIMP+, mirroring G-CIMP in glioma PMID:28726821
  • Confirmed established prostate cancer driver; enriched in primary vs metastatic PRAD tumors (p=0.01, weighted permutation test) in the 1,013-sample WES meta-cohort (prad_p1000). PMID:29610475
  • IDH1 mutation defines the LGG subgroup that clusters separately from GBM by aneuploidy pattern: IDH-mutant LGG is characterized by 1p loss and 19q gain (1p/19q co-deletion), while IDH-wildtype GBM shows chromosome 7 gain and chromosome 10 loss. PMID:29622463

Cancer types (linked)

  • DIFG / ASTR / ODG — defining alteration of IDH-mutant low-grade glioma; tumor volume growth rate ~10% per 6 months on active surveillance, accelerated by CDKN2A/B homozygous deletion PMID:37910594.
  • IHCH — actionable driver; classifier prognostic independent of IDH1 status PMID:38864854.
  • DIFG / glioma — IDH1 p.R132H detected in CSF ctDNA as non-invasive molecular diagnosis PMID:39289779.
  • ASTR / GB — IDH1 mutation status determines epigenetic stability; IDH-mutant astrocytomas undergo progressive GCIMP-high to GCIMP-low methylation loss especially with TMZ/RT treatment, leading to transcriptional programs resembling IDH-wildtype GBM PMID:38117484.
  • ODG — IDH1 mutation confirmed in all six grade II oligodendrogliomas; mutation detected at single-cell resolution by scRNA-seq Bowtie alignment PMID:27806376.

Co-occurrence and mutual exclusivity

  • In 1p19q codeleted oligodendrogliomas, IDH1 mutation co-occurs with TERT promoter mutations, CIC, and FUBP1 alterations; in 1p19q intact astrocytomas it co-occurs with TP53 and ATRX PMID:37910594.
  • In oligodendroglioma, subclonal CIC mutations and 1p/19q co-deletion span all three developmental compartments (stem/progenitor, oligodendrocyte-like, astrocyte-like), each defined relative to the shared IDH1/IDH2-mutant background PMID:27806376.

Therapeutic relevance

  • IDH-targeted therapies (e.g., ivosidenib) motivate the search for surrogate endpoints such as tumor volume growth rate during active surveillance of IDH-mutant LGG PMID:37910594.

Open questions

  • None flagged in the corpus.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:22495314

This page was processed by crosslinker on 2026-05-14. - PMID:22817889

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

This page was processed by crosslinker on 2026-05-14. - PMID:23685749

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:24336570

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:26091043

This page was processed by crosslinker on 2026-05-14. - PMID:26343386

This page was processed by crosslinker on 2026-05-14. - PMID:26544944

This page was processed by crosslinker on 2026-05-14. - PMID:26804919

This page was processed by entity-page-writer on 2026-05-15. - 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:28007021

This page was processed by entity-page-writer on 2026-05-15. - PMID:28162975

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:28481359

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. - PMID:28726821

This page was processed by wiki-cli on 2026-05-15. - PMID:29610475

This page was processed by wiki-cli on 2026-05-15. - PMID:29622463

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