Related Experiment Video
Updated: Jun 7, 2026
Evaluation of Biomarkers in Glioma by Immunohistochemistry on Paraffin-Embedded 3D Glioma Neurosphere Cultures
Published on: January 9, 2019
Cancer-associated IDH mutations: biomarker and therapeutic opportunities
K E Yen1, M A Bittinger, S M Su
1Molecular Oncology, Agios Pharmaceuticals, Cambridge, MA 02139, USA.
Abstract:
The discovery of somatic mutations in the isocitrate dehydrogenase (IDH) enzymes through a genome-wide mutational analysis in glioblastoma represents a milestone event in cancer biology. The nature of the heterozygous, point mutations mapping to arginine residues involved in the substrate binding inspired several research teams to investigate their impact on the biochemical activity of these enzymes. Soon, it became clear that the mutations identified impaired the ability of IDH1 and IDH2 to catalyze the conversion of isocitrate to α-ketoglutarate (αKG), whereas conferring a gain of a novel enzymatic activity leading to the reduction of αKG to the metabolite D2-hydroxyglutarate (D-2HG). Across glioma as well as several hematologic malignancies, mutations in IDH1 and IDH2 have shown prognostic value. Several hypotheses implicating the elevated levels of D-2HG and tumorigenesis, and the therapeutic potential of targeting mutant IDH enzymes will be discussed.
Insights
Somatic mutations in isocitrate dehydrogenase (IDH) enzymes in glioblastoma alter their function, leading to D-2-hydroxyglutarate (D-2HG) production. These IDH mutations are significant in glioma and hematologic malignancies.
Area of Science:
- Biochemistry
- Cancer Biology
- Genetics
Background:
- Somatic mutations in isocitrate dehydrogenase (IDH) enzymes were discovered in glioblastoma.
- These mutations occur at arginine residues critical for substrate binding.
- The discovery marked a significant event in cancer biology.
Purpose of the Study:
- To investigate the impact of IDH mutations on enzyme activity.
- To understand the novel enzymatic activity conferred by these mutations.
- To discuss the role of D-2HG in tumorigenesis and therapeutic potential.
Main Methods:
- Genome-wide mutational analysis in glioblastoma.
- Biochemical assays to study enzyme activity.
- Analysis of prognostic value across malignancies.
Main Results:
- IDH1 and IDH2 mutations impair isocitrate to α-ketoglutarate (αKG) conversion.
- Mutant IDH enzymes gain activity to reduce αKG to D-2-hydroxyglutarate (D-2HG).
- IDH mutations show prognostic value in glioma and hematologic malignancies.
Conclusions:
- Mutant IDH enzymes have altered biochemical functions.
- Elevated D-2HG levels are implicated in tumorigenesis.
- Targeting mutant IDH enzymes presents therapeutic potential.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
02:18Cancer
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...