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MCAT

Unit 2: Lesson 1

Foundation 1: Biomolecules

A genetic mutation with prognostic value for glioblastoma patients

Problem

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 NADPstart superscript, plus, end superscript-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, with a prevalence of roughly 10%. However, the same studies have 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).
Figure 1 Kaplan-Meier survival curve depicting probability of survival for adult GBM patients harboring the wild type (IDH wild-type, blue, 15 months) or mutant gene (IDH mutated, red, 31 months) for isocitrate dehydrogenase (IDH).
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 NADPstart superscript, plus, end superscript, buffer, and isocitrate. Resulting production of NADPH was assayed via spectrophotometry (Figure 2).
Figure 2. Enzymatic activity of mutant and wild type IDH proteins as measured by spectrophotometry.
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.
Based on information presented in the passage, what is the best explanation for why the researchers chose to measure NADPH concentration in cells transfected with just the vector?
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