Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial)

Written2017-07Jean Loup Huret, Philippe Dessen
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH); UMR1170 INSERM, Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France 'PHD)

Abstract Human Isocitrate dehydrogenase (IDH) occurs in three isozymes, IDH1, located in the cytoplasm, and IDH2 and IDH3 located in the mitochondria. IDH functions as part of the tricarboxylic acid (TCA) cycle and catalyzes the reversible conversion of isocitrate to alpha ketoglutarate (α-KG)/2-oxoglutarate (2-OG), thus promoting the activity of dioxygenases that require α-KG as a cosubstrate. IDH1 and IDH2 use NADP+ as a cofactor, producing NADPH in the process (NADPH plays a vital role in the regeneration of the antioxidant glutathione), whereas IDH3 uses NAD+ as a cofactor and produces NADH. Somatic heterozygous mutations in the active site of IDH1 (at position R132) or IDH2 (at position R140 or R172) have been reported in a spectrum of human tumors : gliomas, hematologic malignancies including myeloproliferative neoplasms, myelodysplastic syndromes and acute myeloid leukemia, and also angioimmunoblastic T-cell lymphoma and primary central nervous system lymphoma, cholangiocarcinoma, chondrosarcomas, and other malignancies. IDH mutations lead to a neomorphic enzymatic activity of the mutated IDH enzyme, resulting in the conversion of α-KG to R-2-hydroxyglutarate (R2-HG). Supra-normal levels of intracellular 2-HG interfere with several α-KG-dependent dioxygenases, notably enzymes involved in methylation of histones (histone lysine demethylases, KDMs) and DNA (TET family of DNA hydroxylases).

Keywords Isocitrate dehydrogenase; tricarboxylic acid (TCA) cycle; mitochondrion; NADP binding; oxidoreductase activity; tumorigenesis; gliomas; glioblastomas; astrocytomas; myeloproliferative neoplasms; myelodysplastic syndromes; acute myeloid leukemia; T-cell lymphoma; primary central nervous system lymphoma; cholangiocarcinoma; chondrosarcomas ; Ollier disease, Mafucci disease.

(Note : for Links provided by Atlas : click)


HGNC (Hugo) IDH2
HGNC Previous nameisocitrate dehydrogenase 2 (NADP+), mitochondrial
 isocitrate dehydrogenase (NADP(+)) 2, mitochondrial
LocusID (NCBI) 3418
Atlas_Id 49969
Location 15q26.1  [Link to chromosome band 15q26]
Location_base_pair Starts at 90083046 and ends at 90102468 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping IDH2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). In human, five isocitrate dehydrogenases genes have been reported:
three NAD(+)-dependent isocitrate dehydrogenases (IDH3A, IDH3B, IDH3G) , which localize to the mitochondrial matrix. IDH3 catalyzes the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. IDH3 is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit;
and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial (IDH2) and the other ( IDH1) predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. IDH2 plays a role in intermediary metabolism and energy production and may tightly associate or interact with the pyruvate dehydrogenase complex.


Note Alternative splicing of IDH2 gene results in multiple transcript variants. [provided by RefSeq, Feb 2014]
  Genomic location of the three IDH2 isoforms on chr15q26.3 (build hg19) transcribed in the reverse strand of the genome (UCSC or RefSeq).
Description The various isocitrate dehydrogenases are :
IDH1 isocitrate dehydrogenase 1 (NADP+), an homodimer located in 2q33.3, localized in cytoplasm ,
IDH2 isocitrate dehydrogenase 2 (NADP+), mitochondrial, located in 15q26.1, localized in mitochondria
IDH3 isocitrate dehydrogenase 3 (NAD+) , composed of 3 subunits (IDH3A, 15q25.1) , (IDH3B, 20p13), and IDH3G, Xq28), localized in mitochondrion .
Transcription The sequence of IDH2 is defined by 610 GenBank accessions from 560 cDNA clones, some from brain (seen 50 times), liver (31), prostate (22), testis (20), uterus (19), colon (18), stomach (17) and 141 other tissues (from Acembly).
IDH2 gene has 3 transcript isoforms (RefSeq):
IDH2 at chr15:90627211-90645786 - (NM_002168) isocitrate dehydrogenase [NADP], mitochondrial isoform 1 precursor (Genomic size: 18576; strand -, 11 exons).IDH2 at chr15:90627211-90643853
- (NM_001289910) isocitrate dehydrogenase [NADP], mitochondrial isoform 2 (Genomic size: 16643; strand -, 11 exons).
IDH2 at chr15:90627211-90645786 - (NM_001290114) isocitrate dehydrogenase [NADP], mitochondrial isoform 3 (Genomic size: 18576; strand -, 9 exons).
On the other hand enSembl cites 5 transcripts and 4 phenotypes.
Pseudogene In the human genome exists an IDH1 pseudogene in 6p24, (B4DXS4_HUMAN, chr6: 7516836-7517533 ) homolog of IDH2 (92%) present in monkeys (99.1% identity with the NM_001265779.2 transcript in the case of Rhesus). 


  Structure of the primary sequence of IDH2 with the main features.
Description The 3 IDH2 isoforms have 452, 400 and 332 amino acids (aa) respectively and are homodimers. The differences are in the NH2 part. UNIPROT cites uniquely 2 isoforms (P48735-1, 452 aa, and P48735-2, 400 aa) [ ]. The third isoform deduced from RefSeq lacks 120 NH2 aa.
3D_Structure The first 3D structure solved in human was the homodimer IDH1 (wild type and mutant R132 (UNIPROT:P75874 and PDB: 3mar, Yang et al, 2010). The first structure of mammalia IDH2 was that of Sus Scrofa (UNIPROT: P33198 and PDB: 1wld, Ceccarelli et al, 2002). The 3D structure of human IDH2 (mutated as R140Q) has been realized as a complex with an IDH2 inhibitor (PDB: 4ja8, Wang et al., 2013) by replacement in IDH1 structure. All these structures belong to the superfamily c.77.1: Isocitrate/Isopropylmalate dehydrogenase-like, a class of alpha and beta proteins (a/b) and a fold consisted of two intertwined (sub)domains related by pseudo dyad; the constituent families contains a typical Rossman fold of dehydrogenase to adapt the binding of NAD(P)+ and form similar dimers with the active site between the two identical subunits (
  Comparison of primary structures of mitochondrial (IDH2; P48735) and cytoplasmic (IDH1 ; P75874) isocitrate dhydrogenases (73% identity). * denote the two arginines R140 and R172.
Expression The IDH2 gene is expressed at very high level, 5 times the average gene expression. IDH2 is expressed particularly at higher level in heart, stomach, muscle, thymus, kidney.
  3D structure of the human IDH2 dimer (modelised by SwissModel from Sus Scrofa IDH2 complexed with Mn2+ isocitrate (PDB:1wld) (panel A). Topological secondary structure of IDH2 mutated (PDB:4ja8) (from PDBSum : (panel B) with the position of the two potential mutations (R140 and R172).
Localisation Mitochondrion; Translated in the cytoplasm, IDH2 goes to mitochondrial matrix via a specific transit peptide NH2 (1-45).
  IDH occurs in three isoforms, IDH1, located in the cytoplasm, IDH2 and IDH3, located in the mitochondria, which function as part of the tricarboxylic acid (TCA) cycle or "Krebs cycle" IDH proteins catalyze the oxidative decarboxylation of isocitrate to produce CO2 and alpha-ketogluatarate (α-KG). The reaction requires the presence of the cofactor NADP+ as electron acceptor, generating nicotinamide adenine dinucleotide phosphate (NADPH). IDH1 and IDH2, are homodimeric enzymes.
Function This protein catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate and is specific of NADP(+). IDH2 plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.

Catalytic activity EC: . For the wild type enzyme the catalytic reaction is :

Isocitrate + NADP(+) -> 2-oxoglutarate + CO(2) + NADPH.

In mutated forms (R140 or R172), there is an abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate (2-HG).
Isocitrate + NADP(+) -> 2-hydrocyglutarate + CO(2) + NADPH.

Cofactor Mg(2+); Mn(2+). 1 Mg(2+) or Mn(2+) ion per subunit. Required for activity.
This second specific activity is related to the role of 2-HG as inhibitor of enzymes implicated in demethylation of DNA (TET2 and other demethylases) (Nakajima et al. 2014, Scourzic et al, 2015).

Post translational modification Acetylation at Lys-413 dramatically reduces catalytic activity.

  Role of IDH2 in TCA cycle and of the mutated form in inhibition of demethylation pathways .by competition of 2-HG for the α-KG on TET2 (adapted from Nakajima , 2014).
Homology In molecular biology, the isocitrate/isopropylmalate dehydrogenase family is a protein family consisting of the evolutionary related enzymes isocitrate dehydrogenase, 3-isopropylmalate dehydrogenase and tartrate dehydrogenase. IDH is well conserved in eucaryota in a two separate lineages (cytoplasmic, IDHC or IDH1 and mitochondrial, IDHP or IDH2)(AI et al, 2014). The mammalian NADP+-IDH2 enzyme are structurally compared with the previously solved structures of IDH from E. coli and Bacillus subtilis that share 16 and 17% identity, respectively, with the mammalian enzyme. The mammalian enzyme has a protein fold similar to the bacterial IDH structures with each monomer folding into two domains. However, considerable differences exist between the bacterial and mammalian forms of IDH in regions connecting core secondary structure. In human IDH1 and IDH2 have 72 % identity.


Note The COSMIC database (v75) displays 88 unique mutations for 38867 samples
The main mutations of IDH2 are R140Q and R172K in haematopoeitic and central nervous system neoplasms
  Repartition of IDH2 mutations (in great part on aa R140 and R172) in different sites and tumors (limited to more or equal than 3)
  Mutated IDH1/2 result in the conversion of alpha ketoglutarate (α-KG) to hydroxyglutarate (2-HG). 2-HG acts as an antagonist of α-KG.
  α-KG is a substrate for methyl-cytosine demethylation by TET family proteins (DNA demethylation at CpG islands)
α-KG is a substrate for histone demethylation by Jumonji (JMJ) histone demethylases.

Implicated in

Note Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells. Mutated IDH1/2 results in the conversion of alpha ketoglutarate to hydroxyglutarate (2-HG) an oncometabolite, leading to hypermethylation and a block in cell differentiation
α-KG dependent dioxygenases hydroxylate various substrates and regulate many cellular pathways (collagen, histones, transcription factors, alkylated DNA and RNA, lipids).
2-HG is structurally similar to and acts as an antagonist of α-KG.
High levels of 2-HG lead to hypermethylation, resulting in epigenetic alterations of DNA and histone proteins and in a block in cell differentiation
2-HG competitively inhibits α-KG dependent dioxygenases, including histone/DNA demethylases
  • Jumonji (JMJ) family histone demethylases which control nearly all histone demethylation (for example KDM2A, KDM4A, KDM6A, KDM3B and KDM4C) and
  • methylcytosine dioxygenases of the TET (ten-eleven translocation) family, which play a a key role in the process of DNA demethylation at CpG islands and other sites (Yen et al., 2010; Cairns et al., 2012; Yang et al., 2012; Lemonnier et al., 2016; Mondesir et al., 2016; Stein et al., 2016; Ku and Park, 2017).
    IDH2 mutation induces DNA hypermethylation and inhibits mesenchymal lineage differentiation in correlation with high levels of 2-HG accumulation. IDH2 mutant cells escape contact inhibition (Lu et al. 2013).
    SIRT5 regulates cellular NADPH homeostasis and redox potential by promoting IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense (Zhou et al., 2016). IDH2 downregulation increases NF-?B activation and CHUK (IkBα) phosphorylation and elevates MMP9 activation (Yi et al., 2016).
    Entity Various malignancies
    Note Mutations in IDH1 (in particular c.394C>T encoding a R132C substitution (affecting Arg132) and c.395G>A encoding a R132H substitution) or IDH2 (in particular c.516G>C encoding R172S) occur in 80% of WHO grade II-IV glioma, 60% of chondrosarcoma, 40% of angioimmunoblastic T-cell lymphoma, 20% of acute myeloid leukaemia (AML), 20% of intrahepatic cholangiocarcinoma, 12% of skin melanoma, 10% of acute lymphocytic leukaemia, and 5% of colorectal cancer, see below (Molenaar et al 2017).
    IDH1 mutations are much more frequent than IDH2 mutations in glioma (95%), chondrosarcoma (95%) and cholangiocarcinoma (80%), whereas IDH2 mutations are equally or more frequent in blood malignancies: chronic myeloproliferative diseases (MPD) 2%, myelodysplasia (MDS) 2-7%, acute myeloid leukemia (AML) 8-19%, angioimmunoblastic T-cell lymphoma 20-42%, versus IDH1 mutations: MPD <1%, MDS 2-3%, AML 6-16% (Mondesir et al., 2016). In addition, only IDH2 mutations have been reported in angioimmunoblastic T-cell lymphoma, osteosarcoma and gastric cancer (Molenaar et al., 2015).
    International cancer programs studies demonstrated frequent IDH2 mutations in acute myeloid leukemia, glioma, cholangiocarcinoma and primary central nervous system lymphoma (WHO 9680/3), but also to a lesser extend uterine carcinosarcoma, skin melanoma, and rare mutations in, colorectal carcinoma, bladder urothelial carcinoma, head and neck squamous cell carcinoma, cutaneous squamous cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, renal clear cell carcinoma and renal papillary carcinoma (see Figure below) (cbioportal)
    IDH2 was also reported to be downregulated in melanoma (Park et al., 2008), colon carcinoma (Lu et al., 2012) and osteosarcoma (Yi et al., 2016).
    IDH2 amplification was found mainly in breast cancer, esophageal carcinoma, stomach adenocarcinoma, pancreatic adenocarcinoma, ovarian serous cystadenocarcinoma, uterine corpus carcinoma, neuroendocrine prostate cancer and various other cancers (see second Figure below) (cbioportal).
    Alterations in IDH2 in various cancers (from international cancer programs studies): Green: mutations; Red: amplification; Blue: deletion. Abbreviations: AML: acute myeloid leukemia; PCNSL: primary central nervous system lymphoma; UCS: uterine carcinosarcoma; CSCC: cutaneous squamous cell carcinoma; MDS: myelodysplasia; NEPC: neuroendocrine prostate cancer. Screenshot from
    Mutations in IDH2 in various cancers (from international cancer programs studies): Mutations (red pots) were found in the following: Acute myeloid leukemia, Cholangiocarcinoma, Colorectal carcinoma, Glioma, Head and Neck squamous cell carcinoma, Hepatocellular carcinoma, Lung adeno carcinoma, Skin melanoma, Pancreatic adeno carcinoma, Uterine Carcinosarcoma, Renal Clear cell carcinoma and Renal papillary carcinoma. Screenshot from
    Entity Glioma: Diffuse astrocytic and oligodendrogial tumors and Neuronal and mixed neuronal-glial tumors
    Note The 2016 World Health Organization (WHO) classification of tumors of the central nervous system takes into account IDH1 or IDH2 exon 4 mutations (in IDH1 codon 132 and IDH2 codon 172) as a crucial step in the characterization of gliomas.
    Mutations in IDH1 or IDH2 occur in the vast majority of low-grade gliomas and secondary high-grade gliomas, and they occur early in gliomagenesis. The mutations drive increased methylation in gliomas (Cohen et al., 2013). IDH1 is mutated in 40% of gliomas (roughly 70% of low-grade gliomas, 50% of grade III, and 5 to 10% of primary glioblastomas) in some studies, to 75% in other studies, and IDH2 is mutated in about 2% of gliomas. Most common mutations were: R132H, R132C, R132G, R132S, R132L in IDH1 and R172K, R172M, and R172W in IH2. IDH1/IDH2 mutations are associated with genomic profile, being present in nearly all the 1p19q codeleted gliomas, and virtually absent in gliomas with EGFR amplification. It is a strong and independent predictor of survival (Rossetto et al., 2011; Yang et al., 2012).
    The WHO grade II diffuse astrocytomas and WHO grade III anaplastic astrocytomas are divided into IDH-mutant and IDH-wildtype tumors. The IDH-mutant category is much more frequent. The prognostic differences between IDH-mutant WHO grade II diffuse astrocytomas and WHO grade III anaplastic astrocytomas may not be very different. The prognosis of patients with IDH1/2 mutations has been shown to be significantly better than the prognosis of patients with wild-type IDH1/2 in both grades II diffuse astrocytomas and grade III anaplastic astrocytoma.
    Glioblastomas are divided in the 2016 entral nervous system WHO/OMS classification into IDH-wildtype glioblastoma (90 % of cases), most frequently primary or de novo glioblastoma in patients over 55 years, and IDH-mutant glioblastoma (10 %), most often secondary glioblastoma with a history of prior lower grade diffuse glioma in younger patients. The prognosis of the IDH-mutant cases appears more favorable.
    The diagnosis of oligodendroglioma and anaplastic oligodendroglioma requires the demonstration of both an IDH gene family mutation and combined 1p/19q loss.
    IDH mutations are absent in tumors of childhood that histologically resemble oligodendroglioma, and also in neuronal and mixed neuronal-glial tumors (Louis et al., 2016).
    IDH1 and IDH2 are mutually exclusive in gliomas, and IDH2 mutations are mutually exclusive with PTEN , TP53 and ATRX mutations. Patients with IDH2 mutations had a higher frequency of 1p/19q co-deletion than IDH1 mutant patients (Wang et al., 2016).
    Entity Chronic myeloproliferative syndromes
    Note IDH2 R140Q and IDH2 R172K mutations can occur in 2% of primary myelofibrosis. IDH2 mutations can also occur in polycythemia vera (1.5%) or essential thrombocythemia (<1%) (Tefferi et al., 2010). IDH1/2 mutations confer worse prognosis in patients with myelofibrosis. Primary myelofibrosis with SRSF2 mutations have frequent IDH1 and IDH2 mutations (Lasho et al., 2012).
    Entity Myelodysplastic syndromes (MDS)
    Note IDH2 R140Q and IDH2 R172K mutations have been found in about 6% of cases of refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, chronic myelomonocytic leukemia and secondary acute myeloid leukemia. IDH gene mutations did not have any impact on overall survival (Kosmider et al.,2010).
    Entity Acute myeloid leukemia (AML)
    Note DNMT3A , IDH1, IDH2 and TET proteins play a key role in the process of DNA methylation/demethylation and mutant proteins impairs myeloid differentiation. IDH1/2 and TET2 mutations in acute myeloid leukemia are mutually exclusive in most cases (Paschka et al., 2010; Solary et al., 2014).
    IDH2 mutations are more frequent than IDH1 mutations in AML. IDH2 mutations occur in 9 to 16% of AML cases, according to various large studies. IDH2 mutations are mainly R140Q mutations and R172K mutations. IDH1/2 mutations were associated with older age, lower WBC, higher platelets, normal karyotype, and NPM1 mutations.
    IDH1 mutated cases of myeloid leukemia (MDS and AML) also harbored more DNMT3A, PHF6 and FLT3 mutations, whereas whereas IDH2 mutated cases were enriched in ASXL1, SRSF2 , RUNX1, STAG2 mutations.
    Data on prognostic significance of IDH1/2 mutations in AML has been conflicting. IDH1 or IDH2 mutations may confer sensitivity to novel therapeutic approaches, including the use of demethylating agents (Mardis et al., 2009; Abbas et al., 2010; Paschka et al., 2010; Haferlach et al., 2013; Im et al., 2014; Molenaar et al., 2015).
    Entity Angioimmunoblastic T-cell lymphoma
    Note Angioimmunoblastic T-cell lymphoma (AITL) (WHO 9705/3) is one of the most frequent nodal peripheral T-cell lymphomas.
    Mutations are almost exclusively restricted to IDH2 R172 (Lemonnier et al., 2016).
    IDH2 was mutated (R172K, R172G, R172T, and R140G mutations) in about 20% of angioimmunoblastic T-cell lymphomas, but not in other peripheral B or T-cell leukemia/lymphoma (Hodgkin lymphoma, non-Hodgkin B-cell lymphoma, B-cell acute lymphoblastic lymphoma, T-cell acute lymphoblastic lymphoma, anaplastic large cell lymphoma, enteropathy type T-cell lymphoma, cutaneous T-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal NK/T-cell lymphoma). This is the second most frequent mutation to be identified after TET2 in angioimmunoblastic T-cell lymphoma. It does not show prognostic significance. Overall survival and progression-free survival were identical in patients with wild-type or mutant IDH2 (Cairns et al., 2012).
    Entity Primary central nervous system lymphoma (PCNSL)
    Note Primary central nervous system lymphoma (WHO 9680/3) is a mature B-cell neoplasm. IDH2 mutations were identified in approximately 10% of PCNSL ( see above figures from cbioportal).
    Entity Familial hematological malignancies
    Note Germline IDH mutations were searched for in 104 familial cases of hematological malignancies/cosegregated solid tumors. IDH1 and IDH2 variants were found respectively in 15 % and 3% of cases (Hamadou et al., 2016).
    Entity Cholangiocarcinoma
    Note Cholangiocarcinoma is an aggressive malignancy with poor prognosis. Mutations in IDH1 and IDH2 were found only in 23% of cholangiocarcinomas of intrahepatic origin, in none of the extrahepatic cholangiocarcinomas and rarely (2%) in the other common gastrointestinal malignancies (colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinomas). IDH1 mutations are the most frequent (11%-24%) and IDH2 mutations are seen in 2%-6% of the cases. The IDH1 mutation was R132C, R132L, or R132G, and the IDH2 mutation was R172W, and neither the common glioma mutation R132H of IDH1 nor the common AML mutation at codon R140 of IDH2 was found in cholangiocarcinomas. KRAS, TP53, NRAS, BRAF, AKT1 and PTEN mutations were found each in 3-5% of intrahepatic cholangiocarcinomas (Borger et al., 2012; Borger et al., 2014).
    Entity Chondrosarcoma
    Note 17-24% of primary malignant bone tumors are chondrosarcoma; enchondroma is a benign precursor of chondrosarcoma. While most enchondromas are solitary, patients with Ollier's disease and Maffucci's syndrome (see below) demonstrate multiple enchondromas (Bovée 2002).
    A large retrospective study of Ollier and Maffucci patients was conducted. Overall incidence of development of chondrosarcoma was 40%. Patients with enchondromas located in long bones or axial skeleton, especially the pelvis, have an increased risk of developing chondrosarcoma (Verdegaal et al., 2011).
    More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in IDH1 or IDH2. IDH mutations were associated with DNA hypermethylation at CpG islands enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. Introduction of mutant IDH2 in murine mesenchymal progenitor cells generated undifferentiated sarcomas (Lu et al., 2013).
    Entity Enchondromas, Ollier disease and Maffucci syndrome
    Note Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple central cartilaginous tumors (enchondromas) in Ollier disease, accompanied with soft tissue hemangiomas (spindle cell type) or, less commonly, lymphangiomas in Maffucci syndrome.
    Somatic heterozygous mutations in IDH1 (R132C or R132H substitution) or IDH2 (R172S substitution) were found in 87% of enchondromas and in 70% of spindle cell hemangiomas. About 80% subjects with Ollier disease or Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors (while mutations of PTH1R are found in a 10% of patients with Ollier disease). Mesenchymal tumors, including cartilaginous tumors, osteosarcomas and other bone and soft tissue tumors, were screened for IDH1/IDH2 mutations. Heterozygous somatic IDH1/IDH2 mutations were only detected in central and periosteal cartilaginous tumors, and were found in at least 56% of these. The ratio of IDH1/IDH2 mutation was 10.6/1. No germline mutations were detected. No mutations were detected in peripheral chondrosarcomas and osteochondromas. Low level of mutated DNA was identified in non-neoplastic tissue, a finding compatible with a model in which IDH1 or IDH2 mutations represent early post-zygotic occurrences in Ollier disease and Maffucci syndromes (Amary et al., 2011a; Amary et al., 2011b; Pansuriya et al., 2011).
    IDH2 and TP53 mutations have been found correlated with gliomagenesis in a patient with Maffucci syndrome (Moriya et al., 2014).
    Entity Lung cancer
    Note A higher risk was observed in lung cancer patient carriers of rs11540478 TT and CT compared with CC carriers (Li et al., 2017).
    Entity Breast cancer
    Note Solid papillary carcinoma with reverse polarity is a rare breast cancer subtype. Ten of 13 (77%) solid papillary carcinoma with reverse polarity harbored hotspot mutations at R172 IDH2, of which 8 of 10 also displayed mutations in PIK3CA or PIK3R1 (Chiang et al., 2016).
    Entity D-2-Hydroxyglutaric aciduria
    Note IDH2 mutations were found in a subset of n patients with D-2-hydroxyglutaric aciduria, a neurometabolic inherited disorder. Patients exhibit cardiomyopathy, epilepsy, developmental delay and limited life span (Kranendijk Met al., Science. 2012).
    Entity Parkinson's disease
    Note Reduced IDH2 facilitates apoptotic cell death induction due to elevated mitochondrial oxidative stress and contributes to degeneration of the dopaminergic neuron in the neurotoxin model of Parkinson's disease (Kim et al., 2016).
    Entity Cardiovascular disease
    Note IDH2 functions as an antioxidant and anti-apoptotic protein by supplying NADPH to antioxidant systems. Attenuated IDH2 expression resulted in reactive oxygen species-mediated cell death, which contributes to the pathophysiology of cardiovascular disease and myocardial dysfunction (Ku and Park. 2017), and mutant IDH2 causes cardiomyopathy and neurodegeneration in mice (Akbay, 2014).

    To be noted

    Mutant-IDH1/2 enzymes inhibitors have entered clinical trials for patients with IDH1/2 mutations and represent a novel drug class for targeted therapy (Mondesir et al., 2016; Molenaar et al 2017; Thomas and Majeti. 2017; Shih et al., 2017 Stein et al., 2017; Yen et al., 2017).
    Enasidenib (AG-221/CC-90007), an inhibitor of mutant IDH2, is being explored in a phase I clinical trial for the treatment of AML. AG-221 suppressed 2-HG production and induced cellular differentiation in AML with IDH2 mutations. In clinical trials, safety outcomes for all patients was assessed, a substantial subset of the patients with AML had partial remission and additional patients had a stable disease. Among patients with relapsed or refractory AML, overall response rate was 40% (Stein et al., 2016; Stein et al., 2017). AMLs with mutations in TET2 or IDH2 are sensitive to epigenetic therapy through inhibition of DNA methyltransferase activity of mutant TET2 or inhibition of mutant IDH2 through AG-221. These inhibitors induce a differentiation response (Shih et al., 2017).


    Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value
    Abbas S, Lugthart S, Kavelaars FG, Schelen A, Koenders JE, Zeilemaker A, van Putten WJ, Rijneveld AW, Löwenberg B, Valk PJ
    Blood 2010 Sep 23;116(12):2122-6
    PMID 20538800
    Parallel evolution of IDH2 gene in cetaceans, primates and bats
    Ai WM, Chen SB, Chen X, Shen XJ, Shen YY
    FEBS Lett 2014 Jan 31;588(3):450-4
    PMID 24374336
    D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice
    Akbay EA, Moslehi J, Christensen CL, Saha S, Tchaicha JH, Ramkissoon SH, Stewart KM, Carretero J, Kikuchi E, Zhang H, Cohoon TJ, Murray S, Liu W, Uno K, Fisch S, Jones K, Gurumurthy S, Gliser C, Choe S, Keenan M, Son J, Stanley I, Losman JA, Padera R, Bronson RT, Asara JM, Abdel-Wahab O, Amrein PC, Fathi AT, Danial NN, Kimmelman AC, Kung AL, Ligon KL, Yen KE, Kaelin WG Jr, Bardeesy N, Wong KK
    Genes Dev 2014 Mar 1;28(5):479-90
    PMID 24589777
    IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours
    Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O'Donnell P, Grigoriadis A, Diss T, Eskandarpour M, Presneau N, Hogendoorn PC, Futreal A, Tirabosco R, Flanagan AM
    J Pathol 2011 Jul;224(3):334-43
    PMID 21598255
    Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2
    Amary MF, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F, McCarthy S, Fantin VR, Straley KS, Lobo S, Aston W, Green CL, Gale RE, Tirabosco R, Futreal A, Campbell P, Presneau N, Flanagan AM
    Nat Genet 2011 Nov 6;43(12):1262-5
    PMID 22057236
    Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma
    Borger DR, Goyal L, Yau T, Poon RT, Ancukiewicz M, Deshpande V, Christiani DC, Liebman HM, Yang H, Kim H, Yen K, Faris JE, Iafrate AJ, Kwak EL, Clark JW, Allen JN, Blaszkowsky LS, Murphy JE, Saha SK, Hong TS, Wo JY, Ferrone CR, Tanabe KK, Bardeesy N, Straley KS, Agresta S, Schenkein DP, Ellisen LW, Ryan DP, Zhu AX
    Clin Cancer Res 2014 Apr 1;20(7):1884-90
    PMID 24478380
    Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping
    Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS, Schenkein DP, Hezel AF, Ancukiewicz M, Liebman HM, Kwak EL, Clark JW, Ryan DP, Deshpande V, Dias-Santagata D, Ellisen LW, Zhu AX, Iafrate AJ
    Oncologist 2012;17(1):72-9
    PMID 22180306
    Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2
    Borodovsky A, Seltzer MJ, Riggins GJ
    Curr Opin Oncol 2012 Jan;24(1):83-9
    PMID 22080945
    Genomic landscapes and clonality of de novo AML
    Brewin J, Horne G, Chevassut T
    N Engl J Med 2013 Oct 10;369(15):1472-3
    PMID 24106951
    Human mitochondrial NADP-dependent isocitrate dehydrogenase in man-mouse somatic cell hybrids
    Bruns GA, Eisenman RE, Gerald PS
    Cytogenet Cell Genet 1976;17(4):200-11
    PMID 11969
    IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma
    Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, Parrens M, Martin A, Xerri L, Brousset P, Chan LC, Chan WC, Gaulard P, Mak TW
    Blood 2012 Feb 23;119(8):1901-3
    PMID 22215888
    Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities
    Cairns RA, Mak TW
    Cancer Discov 2013 Jul;3(7):730-41
    PMID 23796461
    Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
    Cancer Genome Atlas Research Network, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ Jr, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, McLellan MD, McMichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, Wartman LD, Watson MA, Welch J, Wendl MC, Ally A, Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez C, Zou L, Leiserson MD, Vandin F, Wu HT, Applebaum F, Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KR, Sheth M, Sofia HJ, Yang L, Downing JR, Eley G
    N Engl J Med 2013 May 30;368(22):2059-74
    PMID 23634996
    Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate
    Ceccarelli C, Grodsky NB, Ariyaratne N, Colman RF, Bahnson BJ
    Insights into the enzyme mechanism J Biol Chem
    PMID 12207025
    Assignment of cytoplasmic alpha-mannosidase (MANA) and confirmation of mitochondrial isocitrate dehydrogenase (IDHM) to the q11 leads to qter region of chromosome 15 in man
    Champion MJ, Brown JA, Shows TB
    Cytogenet Cell Genet 1978;22(1-6):498-502
    PMID 752528
    IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity
    Chiang S, Weigelt B, Wen HC, Pareja F, Raghavendra A, Martelotto LG, Burke KA, Basili T, Li A, Geyer FC, Piscuoglio S, Ng CK, Jungbluth AA, Balss J, Pusch S, Baker GM, Cole KS, von Deimling A, Batten JM, Marotti JD, Soh HC, McCalip BL, Serrano J, Lim RS, Siziopikou KP, Lu S, Liu X, Hammour T, Brogi E, Snuderl M, Iafrate AJ, Reis-Filho JS, Schnitt SJ
    Cancer Res 2016 Dec 15;76(24):7118-7129
    PMID 27913435
    IDH1 and IDH2 mutations in gliomas
    Cohen AL, Holmen SL, Colman H
    Curr Neurol Neurosci Rep 2013 May;13(5):345
    PMID 23532369
    NAD(+)-dependent isocitrate dehydrogenase
    Cupp JR, McAlister-Henn L
    Cloning, nucleotide sequence, and disruption of the IDH2 gene from Saccharomyces cerevisiae J Biol Chem
    PMID 1939242
    New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma
    Dimitrov L, Hong CS, Yang C, Zhuang Z, Heiss JD
    Int J Med Sci 2015 Jan 20;12(3):201-13
    PMID 25678837
    Familial hematological malignancies: new IDH2 mutation
    Hamadou WS, Bourdon V, Létard S, Brenet F, Laarif S, Besbes S, Paci A, David M, Penard-Lacronique V, Youssef YB, Laatiri MA, Eisinger F, Mari V, Gesta P, Dreyfus H, Bonadona V, Dugast C, Zattara H, Faivre L, Noguchi T, Khélif A, Salem CB, Dubreuil P, Sobol H, Soua Z
    Ann Hematol 2016 Dec;95(12):1943-1947
    PMID 27591990
    Assignment of the human mitochondrial NAD+ -specific isocitrate dehydrogenase alpha subunit (IDH3A) gene to 15q25
    Huh TL, Kim YO, Oh IU, Song BJ, Inazawa J
    1-->q25 2by in situ hybridization
    PMID 8833160
    Structure of a bacterial enzyme regulated by phosphorylation, isocitrate dehydrogenase
    Hurley JH, Thorsness PE, Ramalingam V, Helmers NH, Koshland DE Jr, Stroud RM
    Proc Natl Acad Sci U S A 1989 Nov;86(22):8635-9
    PMID 2682654
    DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies
    Im AP, Sehgal AR, Carroll MP, Smith BD, Tefferi A, Johnson DE, Boyiadzis M
    Leukemia 2014 Sep;28(9):1774-83
    PMID 24699305
    Three-dimensional structure of a highly thermostable enzyme, 3-isopropylmalate dehydrogenase of Thermus thermophilus at 2
    Imada K, Sato M, Tanaka N, Katsube Y, Matsuura Y, Oshima T
    2 A resolution J Mol Biol
    PMID 1748999
    Metabolic reprogramming in mutant IDH1 glioma cells
    Izquierdo-Garcia JL, Viswanath P, Eriksson P, Chaumeil MM, Pieper RO, Phillips JJ, Ronen SM
    PLoS One 2015 Feb 23;10(2):e0118781
    PMID 25706986
    IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition
    Kernytsky A, Wang F, Hansen E, Schalm S, Straley K, Gliser C, Yang H, Travins J, Murray S, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, Liu W, Yen KE
    Blood 2015 Jan 8;125(2):296-303
    PMID 25398940
    IDH2 deficiency promotes mitochondrial dysfunction and dopaminergic neurotoxicity: implications for Parkinson's disease
    Kim H, Kim SH, Cha H, Kim SR, Lee JH, Park JW
    Free Radic Res 2016 Aug;50(8):853-60
    PMID 27142242
    IDH2 mutation in gliomas including novel mutation
    Koh J, Cho H, Kim H, Kim SI, Yun S, Park CK, Lee SH, Choi SH, Park SH
    Neuropathology 2015 Jun;35(3):236-44
    PMID 25495392
    Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation
    Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, Losman JA, Joensuu P, Bergmann U, Gross S, Travins J, Weiss S, Looper R, Ligon KL, Verhaak RG, Yan H, Kaelin WG Jr
    Nature 2012 Feb 15;483(7390):484-8
    PMID 22343896
    Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms
    Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B, Hunault-Berger M, Slama B, Vey N, Lacombe C, Solary E, Birnbaum D, Bernard OA, Fontenay M
    Leukemia 2010 May;24(5):1094-6
    PMID 20376084
    Progress in understanding 2-hydroxyglutaric acidurias
    Kranendijk M, Struys EA, Salomons GS, Van der Knaap MS, Jakobs C
    J Inherit Metab Dis 2012 Jul;35(4):571-87
    PMID 22391998
    Downregulation of IDH2 exacerbates H(2)O(2)-mediated cell death and hypertrophy
    Ku HJ, Park JW
    Redox Rep 2017 Jan;22(1):35-41
    PMID 26865387
    SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival
    Lasho TL, Jimma T, Finke CM, Patnaik M, Hanson CA, Ketterling RP, Pardanani A, Tefferi A
    Blood 2012 Nov 15;120(20):4168-71
    PMID 22968464
    Potential mitochondrial isocitrate dehydrogenase R140Q mutant inhibitor from traditional Chinese medicine against cancers
    Lee WY, Chen KC, Chen HY, Chen CY
    Biomed Res Int 2014;2014:364625
    PMID 24995286
    The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development
    Lemonnier F, Cairns RA, Inoue S, Li WY, Dupuy A, Broutin S, Martin N, Fataccioli V, Pelletier R, Wakeham A, Snow BE, de Leval L, Pujals A, Haioun C, Paci A, Tobin ER, Narayanaswamy R, Yen K, Jin S, Gaulard P, Mak TW
    Proc Natl Acad Sci U S A 2016 Dec 27;113(52):15084-15089
    PMID 27956631
    High expression of 5-hydroxymethylcytosine and isocitrate dehydrogenase 2 is associated with favorable prognosis after curative resection of hepatocellular carcinoma
    Liu WR, Tian MX, Jin L, Yang LX, Ding ZB, Shen YH, Peng YF, Zhou J, Qiu SJ, Dai Z, Fan J, Shi YH
    J Exp Clin Cancer Res 2014 Apr 10;33:32
    PMID 24716838
    Isocitrate dehydrogenase 2 mutation is a frequent event in osteosarcoma detected by a multi-specific monoclonal antibody MsMab-1
    Liu X, Kato Y, Kaneko MK, Sugawara M, Ogasawara S, Tsujimoto Y, Naganuma Y, Yamakawa M, Tsuchiya T, Takagi M
    Cancer Med 2013 Dec;2(6):803-14
    PMID 24403254
    Anticancer drugs: IDH2 drives cancer in vivo
    Lokody I
    Nat Rev Drug Discov 2013 Nov;12(11):826-7
    PMID 24172328
    The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary
    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW
    Acta Neuropathol 2016 Jun;131(6):803-20
    PMID 27157931
    Induction of sarcomas by mutant IDH2
    Lu C, Venneti S, Akalin A, Fang F, Ward PS, Dematteo RG, Intlekofer AM, Chen C, Ye J, Hameed M, Nafa K, Agaram NP, Cross JR, Khanin R, Mason CE, Healey JH, Lowe SW, Schwartz GK, Melnick A, Thompson CB
    Genes Dev 2013 Sep 15;27(18):1986-98
    PMID 24065766
    IDH mutation impairs histone demethylation and results in a block to cell differentiation
    Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O'Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, Thompson CB
    Nature 2012 Feb 15;483(7390):474-8
    PMID 22343901
    Expression of human mitochondrial NADP-dependent isocitrate dehydrogenase during lymphocyte activation
    Luo H, Shan X, Wu J
    J Cell Biochem 1996 Mar 15;60(4):495-507
    PMID 8707889
    Altered expression levels of IDH2 are involved in the development of colon cancer
    Lv Q, Xing S, Li Z, Li J, Gong P, Xu X, Chang L, Jin X, Gao F, Li W, Zhang G, Yang J, Zhang X
    Exp Ther Med 2012 Nov;4(5):801-806
    PMID 23226729
    Recurring mutations found by sequencing an acute myeloid leukemia genome
    Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Eldred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, McMichael JF, Meyer RJ, Schindler JK, Pohl CS, Wallis JW, Shi X, Lin L, Schmidt H, Tang Y, Haipek C, Wiechert ME, Ivy JV, Kalicki J, Elliott G, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson MA, Baty J, Heath S, Shannon WD, Nagarajan R, Link DC, Walter MJ, Graubert TA, DiPersio JF, Wilson RK, Ley TJ
    N Engl J Med 2009 Sep 10;361(11):1058-66
    PMID 19657110
    Genomic landscapes and clonality of de novo AML
    Miller CA, Wilson RK, Ley TJ
    N Engl J Med 2013 Oct 10;369(15):1473
    PMID 24106950
    Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours
    Molenaar RJ, Coelen RJ, Khurshed M, Roos E, Caan MW, van Linde ME, Kouwenhoven M, Bramer JA, Bovée JV, Mathôt RA, Klümpen HJ, van Laarhoven HW, van Noorden CJ, Vandertop WP, Gelderblom H, van Gulik TM, Wilmink JW
    BMJ Open 2017 Jun 10;7(6):e014961
    PMID 28601826
    IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives
    Mondesir J, Willekens C, Touat M, de Botton S
    J Blood Med 2016 Sep 2;7:171-80
    PMID 27621679
    IDH2 and TP53 mutations are correlated with gliomagenesis in a patient with Maffucci syndrome
    Moriya K, Kaneko MK, Liu X, Hosaka M, Fujishima F, Sakuma J, Ogasawara S, Watanabe M, Sasahara Y, Kure S, Kato Y
    Cancer Sci 2014 Mar;105(3):359-62
    PMID 24344754
    Isocitrate dehydrogenase (IDH)2 R140Q mutation induces myeloid and lymphoid neoplasms in mice
    Mylonas E, Janin M, Bawa O, Opolon P, David M, Quivoron C, Bernard OA, Ottolenghi C, DeBotton S, Penard-Lacronique V
    Leukemia 2014 Jun;28(6):1343-6
    PMID 24418992
    TET2 as an epigenetic master regulator for normal and malignant hematopoiesis
    Nakajima H, Kunimoto H
    Cancer Sci 2014 Sep;105(9):1093-9
    PMID 25040794
    Novel cases of D-2-hydroxyglutaric aciduria with IDH1 or IDH2 mosaic mutations identified by amplicon deep sequencing
    Nota B, Hamilton EM, Sie D, Ozturk S, van Dooren SJ, Ojeda MR, Jakobs C, Christensen E, Kirk EP, Sykut-Cegielska J, Lund AM, van der Knaap MS, Salomons GS
    J Med Genet 2013 Nov;50(11):754-9
    PMID 24049096
    Assignment of the human mitochondrial NADP(+)-specific isocitrate dehydrogenase (IDH2) gene to 15q26
    Oh IU, Inazawa J, Kim YO, Song BJ, Huh TL
    1 by in situ hybridization Genomics
    PMID 8954790
    IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas
    Olar A, Wani KM, Alfaro-Munoz KD, Heathcock LE, van Thuijl HF, Gilbert MR, Armstrong TS, Sulman EP, Cahill DP, Vera-Bolanos E, Yuan Y, Reijneveld JC, Ylstra B, Wesseling P, Aldape KD
    Acta Neuropathol 2015 Apr;129(4):585-96
    PMID 25701198
    Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome
    Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, Sangiorgi L, Toker B, Liegl-Atzwanger B, San-Julian M, Sciot R, Limaye N, Kindblom LG, Daugaard S, Godfraind C, Boon LM, Vikkula M, Kurek KC, Szuhai K, French PJ, Bovée JV
    Nat Genet 2011 Nov 6;43(12):1256-61
    PMID 22057234
    Inactivation of mitochondrial NADP+-dependent isocitrate dehydrogenase by hypochlorous acid
    Park SY, Lee SM, Shin SW, Park JW
    Free Radic Res 2008 May;42(5):467-73
    PMID 18484410
    IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication
    Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Krönke J, Bullinger L, Späth D, Kayser S, Zucknick M, Götze K, Horst HA, Germing U, Döhner H, Döhner K
    J Clin Oncol 2010 Aug 1;28(22):3636-43
    PMID 20567020
    Prognostic relevance of integrated genetic profiling in acute myeloid leukemia
    Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, Van Vlierberghe P, Dolgalev I, Thomas S, Aminova O, Huberman K, Cheng J, Viale A, Socci ND, Heguy A, Cherry A, Vance G, Higgins RR, Ketterling RP, Gallagher RE, Litzow M, van den Brink MR, Lazarus HM, Rowe JM, Luger S, Ferrando A, Paietta E, Tallman MS, Melnick A, Abdel-Wahab O, Levine RL
    N Engl J Med 2012 Mar 22;366(12):1079-89
    PMID 22417203
    Metabolism of glioma and IDH1/IDH2 mutations
    Rossetto M, Ciccarino P, Boisselier B, Labussiere M, Sanson M
    Rev Neurol (Paris) 2011 Oct;167(10):699-703
    PMID 21885076
    Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer
    Saha SK, Parachoniak CA, Ghanta KS, Fitamant J, Ross KN, Najem MS, Gurumurthy S, Akbay EA, Sia D, Cornella H, Miltiadous O, Walesky C, Deshpande V, Zhu AX, Hezel AF, Yen KE, Straley KS, Travins J, Popovici-Muller J, Gliser C, Ferrone CR, Apte U, Llovet JM, Wong KK, Ramaswamy S, Bardeesy N
    Nature 2014 Sep 4;513(7516):110-4
    PMID 25043045
    TET proteins and the control of cytosine demethylation in cancer
    Scourzic L, Mouly E, Bernard OA
    Genome Med 2015 Jan 29;7(1):9
    PMID 25632305
    Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia
    Shih AH, Meydan C, Shank K, Garrett-Bakelman FE, Ward PS, Intlekofer AM, Nazir A, Stein EM, Knapp K, Glass J, Travins J, Straley K, Gliser C, Mason CE, Yen K, Thompson CB, Melnick A, Levine RL
    Cancer Discov 2017 May;7(5):494-505
    PMID 28193779
    Somatic cell genetic assignment of the human gene for mitochondrial NADP-linked isocitrate dehydrogenase to the long arm of chromosome 15
    Shimizu N, Giles RE, Kucherlapati RS, Shimizu Y, Ruddle FH
    Somatic Cell Genet 1977 Jan;3(1):47-60
    PMID 564083
    The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases
    Solary E, Bernard OA, Tefferi A, Fuks F, Vainchenker W
    Leukemia 2014 Mar;28(3):485-96
    PMID 24220273
    Molecular Pathways: IDH2 Mutations-Co-opting Cellular Metabolism for Malignant Transformation
    Stein EM
    Clin Cancer Res 2016 Jan 1;22(1):16-9
    PMID 26553750
    IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis
    Tefferi A, Lasho TL, Abdel-Wahab O, Guglielmelli P, Patel J, Caramazza D, Pieri L, Finke CM, Kilpivaara O, Wadleigh M, Mai M, McClure RF, Gilliland DG, Levine RL, Pardanani A, Vannucchi AM
    Leukemia 2010 Jul;24(7):1302-9
    PMID 20508616
    Optimizing Next-Generation AML Therapy: Activity of Mutant IDH2 Inhibitor AG-221 in Preclinical Models
    Thomas D, Majeti R
    Cancer Discov 2017 May;7(5):459-461
    PMID 28461409
    Tartrate dehydrogenase, a new member of the family of metal-dependent decarboxylating R-hydroxyacid dehydrogenases
    Tipton PA, Beecher BS
    Arch Biochem Biophys 1994 Aug 15;313(1):15-21
    PMID 8053675
    Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: an international multicenter study of 161 patients
    Verdegaal SH, Bovée JV, Pansuriya TC, Grimer RJ, Ozger H, Jutte PC, San Julian M, Biau DJ, van der Geest IC, Leithner A, Streitbürger A, Klenke FM, Gouin FG, Campanacci DA, Marec-Berard P, Hogendoorn PC, Brand R, Taminiau AH
    Oncologist 2011;16(12):1771-9
    PMID 22147000
    Isocitrate dehydrogenase mutations in gliomas
    Waitkus MS, Diplas BH, Yan H
    Neuro Oncol 2016 Jan;18(1):16-26
    PMID 26188014
    Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation
    Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S, Yen KE
    Science 2013 May 3;340(6132):622-6
    PMID 23558173
    The comparison of clinical and biological characteristics between IDH1 and IDH2 mutations in gliomas
    Wang HY, Tang K, Liang TY, Zhang WZ, Li JY, Wang W, Hu HM, Li MY, Wang HQ, He XZ, Zhu ZY, Liu YW, Zhang SZ
    J Exp Clin Cancer Res 2016 May 31;35:86
    PMID 27245697
    The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate
    Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB
    Cancer Cell 2010 Mar 16;17(3):225-34
    PMID 20171147
    Mutations in the isocitrate dehydrogenase 2 gene and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia
    Willander K, Falk IJ, Chaireti R, Paul E, Hermansson M, Gréen H, Lotfi K, Söderkvist P
    Biomark Res 2014 Oct 8;2:18
    PMID 25324972
    IDH1 and IDH2 mutations in gliomas
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD
    N Engl J Med 2009 Feb 19;360(8):765-73
    PMID 19228619
    Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor-associated mutation R132H
    Yang B, Zhong C, Peng Y, Lai Z, Ding J
    Cell Res 2010 Nov;20(11):1188-200
    PMID 20975740
    IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives
    Yang H, Ye D, Guan KL, Xiong Y
    Clin Cancer Res 2012 Oct 15;18(20):5562-71
    PMID 23071358
    IDH1, a CHOP and C/EBPβ-responsive gene under ER stress, sensitizes human melanoma cells to hypoxia-induced apoptosis
    Yang X, Du T, Wang X, Zhang Y, Hu W, Du X, Miao L, Han C
    Cancer Lett 2015 Sep 1;365(2):201-10
    PMID 26049021
    AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
    Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E, Chen Y, Nagaraja R, Choe S, Jin L, Konteatis Z, Cianchetta G, Saunders JO, Salituro FG, Quivoron C, Opolon P, Bawa O, Saada V, Paci A, Broutin S, Bernard OA, de Botton S, Marteyn BS, Pilichowska M, Xu Y, Fang C, Jiang F, Wei W, Jin S, Silverman L, Liu W, Yang H, Dang L, Dorsch M, Penard-Lacronique V, Biller SA, Su SM
    Cancer Discov 2017 May;7(5):478-493
    PMID 28193778
    Downregulation of IDH2 exacerbates the malignant progression of osteosarcoma cells via increased NF-κB and MMP-9 activation
    Yi WR, Li ZH, Qi BW, Ernest ME, Hu X, Yu AX
    Oncol Rep 2016 Apr;35(4):2277-85
    PMID 26782630
    SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status
    Yu W, Dittenhafer-Reed KE, Denu JM
    J Biol Chem 2012 Apr 20;287(17):14078-86
    PMID 22416140
    Modeling substrate binding in Thermus thermophilus isopropylmalate dehydrogenase
    Zhang T, Koshland DE Jr
    Protein Sci 1995 Jan;4(1):84-92
    PMID 7773180
    SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense
    Zhou L, Wang F, Sun R, Chen X, Zhang M, Xu Q, Wang Y, Wang S, Xiong Y, Guan KL, Yang P, Yu H, Ye D
    EMBO Rep 2016 Jun;17(6):811-22
    PMID 27113762


    This paper should be referenced as such :
    Jean Loup Huret, Philippe Dessen
    IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial)
    Atlas Genet Cytogenet Oncol Haematol. 2018;22(4):123-137.
    Free journal version : [ pdf ]   [ DOI ]

    Other Leukemias implicated (Data extracted from papers in the Atlas) [ 7 ]
      Classification of myelodysplastic syndromes 2015
    Chronic Myelomonocytic Leukemia (CMML)
    Early T-cell precursor acute lymphoblastic leukemia
    Follicular lymphomas of germinal center (B- or T-cell) origin
    Mixed phenotype acute leukemia (MPAL)
    Myelodysplastic syndrome with excess blasts
    Therapy-Related Hematopoietic Neoplasia

    Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
      Familial glioma

    External links


    HGNC (Hugo)IDH2   5383
    LRG (Locus Reference Genomic)LRG_611
    Atlas Explorer : (Salamanque)IDH2
    Entrez_Gene (NCBI)IDH2    isocitrate dehydrogenase (NADP(+)) 2
    AliasesD2HGA2; ICD-M; IDH; IDHM; 
    GeneCards (Weizmann)IDH2
    Ensembl hg19 (Hinxton)ENSG00000182054 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000182054 [Gene_View]  ENSG00000182054 [Sequence]  chr15:90083046-90102468 [Contig_View]  IDH2 [Vega]
    ICGC DataPortalENSG00000182054
    TCGA cBioPortalIDH2
    AceView (NCBI)IDH2
    Genatlas (Paris)IDH2
    SOURCE (Princeton)IDH2
    Genetics Home Reference (NIH)IDH2
    Genomic and cartography
    GoldenPath hg38 (UCSC)IDH2  -     chr15:90083046-90102468 -  15q26.1   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)IDH2  -     15q26.1   [Description]    (hg19-Feb_2009)
    GoldenPathIDH2 - 15q26.1 [CytoView hg19]  IDH2 - 15q26.1 [CytoView hg38]
    Genome Data Viewer NCBIIDH2 [Mapview hg19]  
    OMIM147650   613657   
    Gene and transcription
    Genbank (Entrez)AK222916 AK294148 AK299987 AK312627 AK316388
    RefSeq transcript (Entrez)NM_001289910 NM_001290114 NM_002168
    Consensus coding sequences : CCDS (NCBI)IDH2
    Gene ExpressionIDH2 [ NCBI-GEO ]   IDH2 [ EBI - ARRAY_EXPRESS ]   IDH2 [ SEEK ]   IDH2 [ MEM ]
    Gene Expression Viewer (FireBrowse)IDH2 [ Firebrowse - Broad ]
    GenevisibleExpression of IDH2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)3418
    GTEX Portal (Tissue expression)IDH2
    Human Protein AtlasENSG00000182054-IDH2 [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP48735   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtP48735  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProP48735
    Catalytic activity : Enzyme1.1.1.42 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   [ MEROPS ]
    Domaine pattern : Prosite (Expaxy)IDH_IMDH (PS00470)   
    Domains : Interpro (EBI)IsoCit/isopropylmalate_DH_CS    Isocitrate_DH_NADP    IsoPropMal-DH-like_dom   
    Domain families : Pfam (Sanger)Iso_dh (PF00180)   
    Domain families : Pfam (NCBI)pfam00180   
    Domain families : Smart (EMBL)Iso_dh (SM01329)  
    Conserved Domain (NCBI)IDH2
    PDB (RSDB)4JA8    5GIS    5I95    5I96    5SVN    5SVO    6ADI    6VFZ   
    PDB Europe4JA8    5GIS    5I95    5I96    5SVN    5SVO    6ADI    6VFZ   
    PDB (PDBSum)4JA8    5GIS    5I95    5I96    5SVN    5SVO    6ADI    6VFZ   
    PDB (IMB)4JA8    5GIS    5I95    5I96    5SVN    5SVO    6ADI    6VFZ   
    Structural Biology KnowledgeBase4JA8    5GIS    5I95    5I96    5SVN    5SVO    6ADI    6VFZ   
    SCOP (Structural Classification of Proteins)4JA8    5GIS    5I95    5I96    5SVN    5SVO    6ADI    6VFZ   
    CATH (Classification of proteins structures)4JA8    5GIS    5I95    5I96    5SVN    5SVO    6ADI    6VFZ   
    AlphaFold pdb e-kbP48735   
    Human Protein Atlas [tissue]ENSG00000182054-IDH2 [tissue]
    Protein Interaction databases
    DIP (DOE-UCLA)P48735
    IntAct (EBI)P48735
    Ontologies - Pathways
    Ontology : AmiGOmagnesium ion binding  isocitrate dehydrogenase (NADP+) activity  isocitrate dehydrogenase (NADP+) activity  isocitrate dehydrogenase (NADP+) activity  mitochondrion  mitochondrion  mitochondrion  mitochondrial matrix  peroxisome  cytosol  carbohydrate metabolic process  glyoxylate cycle  tricarboxylic acid cycle  isocitrate metabolic process  isocitrate metabolic process  2-oxoglutarate metabolic process  NADP metabolic process  NAD binding  extracellular exosome  
    Ontology : EGO-EBImagnesium ion binding  isocitrate dehydrogenase (NADP+) activity  isocitrate dehydrogenase (NADP+) activity  isocitrate dehydrogenase (NADP+) activity  mitochondrion  mitochondrion  mitochondrion  mitochondrial matrix  peroxisome  cytosol  carbohydrate metabolic process  glyoxylate cycle  tricarboxylic acid cycle  isocitrate metabolic process  isocitrate metabolic process  2-oxoglutarate metabolic process  NADP metabolic process  NAD binding  extracellular exosome  
    REACTOMEP48735 [protein]
    REACTOME PathwaysR-HSA-71403 [pathway]   
    NDEx NetworkIDH2
    Atlas of Cancer Signalling NetworkIDH2
    Wikipedia pathwaysIDH2
    Orthology - Evolution
    GeneTree (enSembl)ENSG00000182054
    Phylogenetic Trees/Animal Genes : TreeFamIDH2
    Homologs : HomoloGeneIDH2
    Homology/Alignments : Family Browser (UCSC)IDH2
    Gene fusions - Rearrangements
    Fusion : FusionGDB1.1.1.42   
    Fusion : FusionHubIDH2--C2    IDH2--FANCI    IDH2--IDH1    IDH2--IDH2    IDH2--KIF1C    IDH2--KIRREL3    IDH2--MIF    IDH2--PMPCA    IDH2--RP11-617F23.1    IDH2--RPS11   
    IDH2--SLC35E2B    IDH2--VPS26B    NDUFA3--IDH2    NRAS--IDH2    RBM6--IDH2    RPS11--IDH2    SEMA4B--IDH2   
    Fusion : QuiverIDH2
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerIDH2 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)IDH2
    Exome Variant ServerIDH2
    GNOMAD BrowserENSG00000182054
    Varsome BrowserIDH2
    ACMGIDH2 variants
    Genomic Variants (DGV)IDH2 [DGVbeta]
    DECIPHERIDH2 [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisIDH2 
    ICGC Data PortalIDH2 
    TCGA Data PortalIDH2 
    Broad Tumor PortalIDH2
    OASIS PortalIDH2 [ Somatic mutations - Copy number]
    Cancer Gene: CensusIDH2 
    Somatic Mutations in Cancer : COSMICIDH2  [overview]  [genome browser]  [tissue]  [distribution]  
    Somatic Mutations in Cancer : COSMIC3DIDH2
    Mutations and Diseases : HGMDIDH2
    intOGen PortalIDH2
    LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
    DgiDB (Drug Gene Interaction Database)IDH2
    DoCM (Curated mutations)IDH2
    CIViC (Clinical Interpretations of Variants in Cancer)IDH2
    NCG (London)IDH2
    Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    OMIM147650    613657   
    Orphanet17509    2257    19664    19671    19672    19652    19655    19657    19656    19663    11341   
    Genetic Testing Registry IDH2
    NextProtP48735 [Medical]
    Target ValidationIDH2
    Huge Navigator IDH2 [HugePedia]
    Clinical trials, drugs, therapy
    Protein Interactions : CTDIDH2
    Pharm GKB GenePA29631
    Clinical trialIDH2
    canSAR (ICR)IDH2
    DataMed IndexIDH2
    PubMed428 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

    Search in all EBI   NCBI

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Thu Jan 20 14:09:22 CET 2022

    Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

    For comments and suggestions or contributions, please contact us