Gene mutation: IDH mutation in glioblastoma

Glioblastoma multiforme (GBM), the most common brain malignancy in adults, arises from genetic alterations in the glial cells of the central nervous system and carries a prognosis of certain death based on currently available treatments (surgical resection, chemotherapy, radiation). Recent advances in high-throughput genetic sequencing and bioinformatics have led to the identification of a mutation in the gene for the enzyme NADP${}^{+}$‍-specific isocitrate dehydrogenase (referred to here as IDH) that affects survival in GBM patients. Genetic analysis of tissue samples indicates that the IDH mutation in GBM tumors is relatively rare, with a prevalence of roughly 10%. However, the same studies found that the IDH mutation is found in roughly 80% of GBM tumors that began as lower grade gliomas and progressed to GBM status over time (so-called secondary GBM).

The Kaplan-Meier survival curves depicting probability of survival of GBM patients with and without the IDH mutation are shown in Figure 1.

Figure 1 Survival curves for adult GBM patients harboring the wild-type (wt) or mutated IDH gene

In order to determine the biological consequences of IDH mutations in GBM, researchers transfected a human oligodendroglioma cell line with a vector containing either the wild-type (wt) IDH gene or the mutant IDH gene. The resulting cells were cultured for 48 hours in growth media, lysed, and centrifuged. The same process was also applied to cells transfected with a control vector lacking the IDH gene. The supernatants from each of the three cell lines were separately combined with NADP${}^{+}$‍, buffer, and isocitrate. NADPH levels were then measured spectrophotometrically. The results are shown in Figure 2.

Figure 2 NADPH production in transfected cells

In addition to providing useful prognostic information to clinicians and patients, the discovery of IDH mutations in GBM tumors provides a potential biological explanation for the existence of secondary GBM.