Isocitrate dehydrogenase mutations may be a protective mechanism in glioma patients.

Gliomas are the most common human brain tumours and can be classified into four grades based on clinical and pathological criteria. A recent cancer genome-sequencing project revealed that more than 70% of low-grade gliomas bear mutations in one of two NAD(+)-dependent isocitrate dehydrogenase enzymes, namely, IDH1 and IDH2. Based on the findings that glioma-derived mutations in IDH1 can inhibit the catalytic activity of the enzyme, induce HIF-1α, and can produce 2-hydroxyglutarate, two research groups speculated that the IDH mutations may contribute to the promotion of tumorigenesis in gliomas. However, they cannot fully explain the phenomenon that patients harbouring such mutations usually have better outcomes than those with the wild-type IDH genes. This fact leads us to hypothesize that the IDH mutations are not the origin of gliomas but a subsequent protective mechanism that interferes with the metabolism of the tumour cells, making these cells fragile and susceptible to cell death. This process finally helps patients who harbour such IDH mutations to survive. Therefore, contrary to the proposals of other researchers, we speculate that any interventions that correct the impaired function of the mutant IDHs, such as the use of cell-permeable α-ketoglutarate derivatives, may not cure gliomas and may even worsen the disease.