Three papers studying the role of specific mutations in brain cancers are published in Nature this week. The studies uncover a mechanistic framework for how mutations in the isocitrate dehydrogenase (IDH) genes may be involved in the development of cancers.

Isocitrate dehydrogenases (IDHs) are enzymes involved in chemical reactions that generate energy within cells. Mutations in IDH have been identified in several cancer types, including gliomas — cancers that originate in the glial cells in the brain.

Timothy Chan and co-workers show that mutation of IDH1 promotes epigenetic changes to the DNA in glial cells, and these epigenetic alterations are the same as those found in a certain subclass of glioma. Their findings provide a possible pathway linking IDH mutations to the formation of tumours.

In a second study, Craig Thompson and colleagues find other epigenetic changes resulting from expression of mutant IDH enzymes. Mutant IDH produces the metabolite 2-hydroxyglutarate (2HG), which impairs demethylation of histones and prevents cells from differentiating normally, and thus could contribute to tumour development.

William Kaelin and co-authors also investigate the role of 2HG in the development of cancer, which has previously been shown to inhibit the activity of several enzymes. However, Kaelin and colleagues find that another enzyme involved in the hypoxia pathway is activated by the (R)-enantiomer of 2HG, which they show to enhance cell proliferation.

Taken together, these studies imply that IDH mutations alter the activity of several cellular enzymes, leading to changes which may be important in the development of tumours.

Source: Nature