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CLICK IMAGE FOR MORE INFORMATIONThe IDH1 gene encodes an enzyme called isocitrate dehydrogenase 1, found in the compartment of cells called the cytoplasm. This enzyme is normally involved in the transfer of energy from one molecule to another during certain biochemical reactions within the cell.
Mutations involving the IDH1 gene have been found in various cancers, including Acute Myeloid Leukemia (AML), intrahepatic bile duct cancers (Cholangiomas), Chondrosarcomas, and specific brain tumors (gliomas and glioblastomas). These alterations cause the amino acid (protein building block) arginine to be replaced by a different amino acid at a key position in the long chain of amino acids that make up this protein. The change in amino acid sequence alters the structure of the protein, resulting in loss of its normal function. Instead of its' normal metabolic product, the mutated IDH1 produces a new metabolite, R (-)-2-hydroxyglutarate, also called 2-HG. 2HG inhibits Tet and KGM enzymes, which alter the organization of DNA and disrupt normal gene expression patterns. These changes contribute directly to the development of cancer.
Tumor mutation profiling performed clinically at the MGH Cancer Center has identified the highest incidence of IDH1 mutations in brain tumors called gliomas (50-60%) and glioblastomas (~10%), cholangiocarcinomas (18-25%), chondrosarcomas, and Acute Myeloid Leukemia (5-10%).
The IDH1 gene encodes for the metabolic enzyme isocitrate dehydrogenase 1. This enzyme is located in the cytoplasm and peroxisomes of cells, and normally functions to catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, with the production of NADPH.
Recurrent mutations in IDH1 occur primarily at codon 132. These mutations result in decreased normal enzymatic activity, while conferring neomorphic activity that produces the oncometabolite R(-)-2-hydroxyglutarate (2HG) as the end-product. Levels of 2HG can accumulate dramatically in IDH1-mutant tumors and this is thought to promote tumorigenesis by competitively inhibiting the activity of a number of dioxygenases. The net effect appears to involve the promotion of gene silencing through hypermethylation of DNA and histones, as well as the activation of the hypoxia-inducible factor signaling pathway.
Tumor genotype testing performed clinically at the MGH Cancer Center has identified the highest incidence of IDH1 mutations in low-grade gliomas (50-60%), glioblastomas (~10%), cholangiocarcinomas (18-25%), chondrosarcomas, and acute myeloid leukemias (5-10%).
PubMed ID's
22234630,
22180306Preclinical Research has demonstrated that some cancers harbor mutations in IDH1 gene that result in altered amino acids in position 132 of the protein. These include R132C (c.394 C>T); R132G (c.394 C>G); R132H (c.395 G>A); R132L (c.395 G>T); and R132S (c.394 C>A); All result in altered activity in the enzyme, producing 2-HG instead of the metabolic product produced by the normal enzyme.
Preclinical Research has demonstrated that some cancers harbor mutations in IDH1 gene that result in altered amino acids in position 132 of the protein. These include R132C (c.394 C>T); R132G (c.394 C>G); R132H (c.395 G>A); R132L (c.395 G>T); and R132S (c.394 C>A); All result in altered activity in the enzyme, producing 2-HG instead of the metabolic product produced by the normal enzyme.