Specific mutations in the isocitrate dehydrogenase gene IDH1 have been found in several brain tumors including astrocytoma, oligodendroglioma and glioblastoma multiforme, with mutations found in nearly all cases of secondary glioblastomas, which develop from lower-grade gliomas, but rarely in primary high-grade glioblastoma multiforme.
Patients whose tumor had an IDH1 mutation had longer survival.
Furthermore, mutations of IDH2 and IDH1 were found in up to 20% of cytogenetically normal acute myeloid leukemia (AML).
These mutations are known to produce (D)-2-hydroxyglutarate from alpha-ketoglutarate. (
D)-2-hydroxyglutarate accumulates to very high concentrations which inhibits the function of enzymes that are dependent on alpha-ketoglutarate.
This leads to a hypermethylated state of DNA and histones, which results in different gene expression that can activate oncogenes and inactivate tumor-suppressor genes.
Ultimately, this may lead to the types of cancer described above.
Somatic mosaic mutations of this gene have also been found associated to Ollier disease and Maffucci syndrome.
However, recent studies have also shown that (D)-2-hydroxyglutarate may be converted back into alpha-ketoglutarate either enzymatically or non-enzymatically.
Further studies are required to fully understand the roles of IDH1 mutation (and (D)-2-hydroxyglutarate) in cancer.
Specific mutations in the isocitrate dehydrogenase gene IDH1 have been found in several brain tumors including astrocytoma, oligodendroglioma and glioblastoma multiforme, with mutations found in nearly all cases of secondary glioblastomas, which develop from lower-grade gliomas, but rarely in primary high-grade glioblastoma multiforme. Patients whose tumor had an IDH1 mutation had longer survival. Furthermore, mutations of IDH2 and IDH1 were found in up to 20% of cytogenetically normal acute myeloid leukemia (AML). These mutations are known to produce (D)-2-hydroxyglutarate from alpha-ketoglutarate. (D)-2-hydroxyglutarate accumulates to very high concentrations which inhibits the function of enzymes that are dependent on alpha-ketoglutarate. This leads to a hypermethylated state of DNA and histones, which results in different gene expression that can activate oncogenes and inactivate tumor-suppressor genes. Ultimately, this may lead to the types of cancer described above. Somatic mosaic mutations of this gene have also been found associated to Ollier disease and Maffucci syndrome. However, recent studies have also shown that (D)-2-hydroxyglutarate may be converted back into alpha-ketoglutarate either enzymatically or non-enzymatically. Further studies are required to fully understand the roles of IDH1 mutation (and (D)-2-hydroxyglutarate) in cancer.
Isocitrate dehydrogenase