15q26.1

D2HGA2,ICD-M,IDH,IDHM,IDP,IDPM,mNADP-IDH

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).

Various malignancies

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

Glioma: Diffuse astrocytic and oligodendrogial tumors and Neuronal and mixed neuronal-glial tumors

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).

Chronic myeloproliferative syndromes

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 (

Myelodysplastic syndromes (MDS)

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).

Acute myeloid leukemia (AML)

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).

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).

Primary central nervous system lymphoma (PCNSL)

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).

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).

Cholangiocarcinoma

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).

Chondrosarcoma

17-24% of primary malignant bone tumors are chondrosarcoma; enchondroma is a benign precursor of chondrosarcoma. While most enchondromas are solitary, patients with Olliers disease and Maffuccis 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).

Enchondromas, Ollier disease and Maffucci syndrome

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).

Lung cancer

A higher risk was observed in lung cancer patient carriers of rs11540478 TT and CT compared with CC carriers (Li et al., 2017).

Breast cancer

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).

D-2-Hydroxyglutaric aciduria

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).

Parkinsons disease

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 Parkinsons disease (Kim et al., 2016).

Cardiovascular disease

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).