A genetic mutation with prognostic value for glioblastoma patients

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 is associated with increased survival for patients harboring the mutation (median survival of $15$‍ months vs. $31$‍ months, Figure 1). Genetic analysis of tissue samples indicate that IDH mutation in GBM tumors is relatively rare, suggesting a prevalence of roughly $10\mathrm{\%}$‍. However, the same studies have found that the IDH mutation is found in roughly $80\mathrm{\%}$‍ of GBM tumors that began as lower grade gliomas and progressed to GBM status over time (so-called secondary GBM).

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 that did not contain the IDH gene or its mutant variant). The supernatant from each of the three cell lines were separately combined with NADP${}^{+}$‍, buffer, and isocitrate. Resulting production of NADPH was assayed via spectrophotometry (Figure 2).

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.

Passage and figures adapted from: Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., . . . Bigner, D. D. (2009). IDH1 and IDH2 mutations in gliomas. N Engl J Med, 360(8), 765-773.