Overview
Isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are key metabolic enzymes involved in the citric acid cycle. IDH1 is located on chromosome 2 and functions mainly in the cytosol, while IDH2 is located on chromosome 15 and functions within the mitochondrial matrix. Under normal conditions, both enzymes catalyze the conversion of isocitrate to α-ketoglutarate and generate NADPH, which is essential for maintaining cellular redox balance.
Mutations in IDH1 and IDH2 define distinct molecular subtypes of cancer. These mutations are commonly seen in low-grade gliomas, secondary glioblastomas, chondrosarcomas, intrahepatic cholangiocarcinomas, and several hematologic malignancies, particularly acute myeloid leukemia (AML). The most common IDH1 mutation involves the substitution of arginine at position 132, resulting in altered enzyme function. IDH mutations have major diagnostic, prognostic, and therapeutic implications. IDH1IDH2 Gene Mutation
Biological Role of IDH1 and IDH2
Under physiological conditions, IDH1 and IDH2 play a crucial role in cellular metabolism. They convert isocitrate into α-ketoglutarate while generating NADPH, which protects cells from oxidative stress and supports biosynthetic reactions.
When mutated, IDH1 and IDH2 acquire a gain-of-function activity. Instead of producing α-ketoglutarate, the mutant enzymes generate an oncometabolite called 2-hydroxyglutarate (2-HG). Accumulation of 2-HG leads to epigenetic dysregulation, impaired cellular differentiation, and tumorigenesis. This abnormal metabolic rewiring is a key driver of cancer development in IDH-mutant tumors.
Common IDH1 and IDH2 Mutations
The most frequent IDH1 mutation is R132H, commonly observed in gliomas, AML, and chondrosarcoma. Other less frequent IDH1 mutations include R132C, R132G, R132S, and R132L, which are seen in gliomas, cholangiocarcinoma, and hematologic malignancies.
IDH2 mutations primarily involve codons R140 and R172. The R140Q mutation is most commonly associated with AML, while R172 mutations are seen in gliomas and chondrosarcomas. These mutation patterns help classify tumor types and guide molecular diagnosis.
Tumors Associated with IDH Mutations
IDH1 and IDH2 mutations are found in a wide spectrum of tumors. In the central nervous system, IDH1 mutations are characteristic of astrocytomas, oligodendrogliomas, anaplastic gliomas, and secondary glioblastomas. IDH-mutant gliomas generally have a better prognosis than IDH-wildtype tumors.
In hematologic malignancies, IDH mutations are commonly seen in AML, myelodysplastic syndromes, myeloproliferative neoplasms, and angioimmunoblastic T-cell lymphoma. IDH2 mutations are particularly frequent in AML. Chondrosarcomas and intrahepatic cholangiocarcinomas also show a significant association with IDH mutations.
Symptoms
IDH1 and IDH2 mutations do not produce specific symptoms by themselves. Clinical manifestations depend on the type, location, and stage of the tumor.
Patients with IDH-mutant gliomas may present with headaches, seizures, neurological deficits, or cognitive changes. In hematologic malignancies, symptoms may include fatigue, infections, bleeding tendencies, or anemia. Molecular testing is required to identify IDH mutation status, as symptoms alone cannot differentiate mutant from wild-type disease.
Methods of Detection
Detection of IDH mutations requires molecular or immunohistochemical techniques. DNA is extracted from tumor tissue, blood, or bone marrow samples.
Common methods include PCR amplification followed by Sanger sequencing, real-time PCR with high-resolution melting analysis, and next-generation sequencing. Immunohistochemistry using an antibody specific for the IDH1 R132H mutation is widely used as a screening tool in gliomas. Positive or equivocal cases are often confirmed by molecular methods.
Sample Collection
Samples for IDH testing include formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks or slides. Blood, bone marrow, or trephine biopsy samples may be collected in EDTA, heparin, or ACD tubes.
Decalcified specimens are not recommended due to DNA damage. Proper sample handling is essential to ensure accurate molecular analysis and reliable results.
Prognostic Significance
IDH mutation status is a strong prognostic marker. In gliomas, IDH-mutant tumors are associated with longer overall survival and progression-free survival compared to IDH-wildtype tumors.
In AML, IDH mutations influence prognosis and help identify patients who may benefit from targeted therapy. IDH-wildtype status is generally associated with poorer prognosis, while IDH-mutant status indicates a more favorable outcome in many tumor types.
Therapeutic Implications
IDH mutations have become important therapeutic targets. Targeted inhibitors such as ivosidenib for IDH1-mutant cancers and enasidenib for IDH2-mutant AML are approved for clinical use.
Vorasidenib, an oral inhibitor targeting both IDH1 and IDH2, has shown effectiveness in gliomas and is capable of crossing the blood–brain barrier. These therapies reduce 2-HG levels, restore cellular differentiation, and represent a major advancement in precision oncology.
Clinical Significance
IDH1 and IDH2 mutation testing is essential for tumor classification, prognosis assessment, and treatment selection. It helps distinguish primary from secondary glioblastomas, identifies specific AML subtypes, and guides targeted therapy decisions.
Overall, IDH mutation analysis has transformed cancer diagnosis and management by linking metabolic alterations to precision medicine and improved patient outcomes.
