IDH mutation in glioblastoma
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IDH mutation in glioblastoma
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[ID] => 553853
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[post_date] => 2024-12-23 09:12:29
[post_date_gmt] => 2024-12-23 14:12:29
[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
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.
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.
[post_title] => IDH mutation in glioblastoma
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[question] => 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?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
The passage indicates that the experiment was carried out using a cell line derived from a human oligodendroglioma tumor.
So, measurement of NADPH concentration in cells transfected with just the vector quantifies basal NADPH production in wild-type eukaryotic cells.
Transfection with just the vector will not introduce or remove any genes to/from the genomes of the cells that take up the vector.
As they are, these eukaryotic cells DO contain the endogenous IDH gene, as the passage makes no mention of these being IDH knockouts or anything of the sort.
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[answers] => Array
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[each_answer] => A. Measurement of NADPH concentration in cells transfected with just the vector quantifies basal NADPH production in wild-type eukaryotic cells, which lack the endogenous IDH gene.
)
[1] => Array
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[each_answer] => B. Measurement of NADPH concentration in cells transfected with just the vector quantifies basal NADPH production in wild-type eukaryotic cells, which have the endogenous IDH gene.
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[2] => Array
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[each_answer] => C. Measurement of NADPH concentration in cells transfected with just the vector quantifies basal NADPH production in wild-type prokaryotic cells, which have the endogenous IDH gene.
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[3] => Array
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[each_answer] => D. Measurement of NADPH concentration in cells transfected with just the vector quantifies basal NADPH production in wild-type prokaryotic cells, which lack the endogenous IDH gene.
)
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => Like all types of cancer, GBM is best characterized by which of the following cellular pathologies?
[value] => Array
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[answer] => 4
[description] => Reason for Correct Answer:
Oncogenes are genes that have the potential, if rendered constitutively active or overexpressed by genetic mutation, to cause the uncontrolled growth of cells. If rendered inactive, it will not contribute to cell growth.
Tumor suppressor genes are genes that code for proteins that prevent the uncontrolled growth of cells; their loss of function often contributes to cancer development. If a tumor suppressor gene is up-regulated or rendered constitutively active by genetic mutation, it will most likely prevent uncontrolled growth of cells.
Apoptosis is the process of programmed cell death. A gain-of-function mutation in a gene controlling apoptosis would lead to the opposite of uncontrolled cell growth.
The only thing that would promote GBM is changes in basal cellular protein levels leading to loss of cell cycle control, which would lead to the uncontrolled growth of cancer cells.
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[each_answer] => A. Loss-of-function mutations in oncogenes
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[each_answer] => B. Gain-of-function mutations in tumor suppressor genes
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[2] => Array
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[each_answer] => C. Gain-of-function mutations in genes controlling apoptosis
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[each_answer] => D. Changes in basal cellular protein levels leading to loss of cell cycle control
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => Assuming that the IDH mutation discussed in the passage confers a loss of function on the protein associated with the gene, which of the following would be the most likely immediate effect in cancer cells harboring the IDH mutation?
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[answer] => 1
[description] => Reason for Correct Answer:
The normal function of the IDH enzyme is to reduce NADP⁺ to NADPH.
In an oxidation-reduction reaction, the molecule that is reduced gains electrons, while the molecule that is oxidized loses electrons.
A loss-of-function mutation in the IDH gene would decrease the ability of IDH to reduce NADP⁺, resulting in less NADPH.
The graph (Figure 2) also shows that the presence of the mutated IDH results in less NADPH than the wild type IDH.
This means that the IDH mutation results in a decrease in the concentration of electron-donating molecules.
NADPH is an electron-donating molecule that is involved in anabolic reactions, where it donates electrons to help reduce molecules, storing energy in the form of chemical bonds.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. Decreased concentration of electron-donating molecules
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[1] => Array
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[each_answer] => B. Decreased concentration of electron-accepting molecules
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[each_answer] => C. Decreased concentration of proton-donating molecules
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[each_answer] => D. Decreased concentration of proton-accepting molecules
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[quiz_unique_key] => 1403770772
[question] => Suppose that researchers chose to assay IDH enzyme activity using the same methods stated in the passage, except that a cell line derived from a GBM patient harboring the IDH mutation was used in place of the cell line used in the original experiment. What changes would they most likely see with respect to the results depicted in Figure 2?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
A cell line derived from GBM cells containing the IDH mutation would have an impeded ability to reduce NADP⁺ to NADPH.
There are other metabolic enzymes that catalyze the reduction of NADP⁺ to NADPH. Thus, it is not reasonable to assume that the assays would find zero NADPH concentration in any of the three separate trials.
There should be a difference between “vector + wt IDH” group and the “vector” and “vector + mutant IDH” groups, as the “vector + wt IDH” group will have the IDH gene re-introduced.
They would most likely find reduced NADPH production in the “vector + wt IDH” group, the “vector” group, and the “vector + mutant IDH” group. This is because you’d be taking away the baseline IDH activity from all these groups.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Reduced NADPH concentration in the “vector + wt IDH” group; no measurable NADPH concentration in the “vector” and “vector + mutant IDH” groups
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[each_answer] => B. Reduced NADPH concentration in the “vector + wt IDH” group, the “vector” group, and the “vector + mutant IDH” group
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[each_answer] => C. No change in NADPH concentration in the “vector + wt IDH” group; no measurable NADPH concentration in the “vector” and “vector + mutant IDH” groups
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[each_answer] => D. No difference in NADPH production between the “vector + wt IDH” group and the “vector” and “vector + mutant IDH” groups
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[quiz_unique_key] => 1403770772
[question] => The observed differences in IDH mutation prevalence in different types of glioma patients indicate that:
[value] => Array
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[answer] => 3
[description] => Reason for Correct Answer:
The information provided suggests that the IDH mutation is relatively rare in primary GBM tumors (tumors that start as GBM) but more prevalent in secondary GBM tumors that originated from lower grade gliomas but developed or transformed into higher grade GBM.
Since the survival curve shows better survival for patients who have the IDH mutation, this certainly does not indicate that secondary GBM patients have worse survival.
This also doesn’t suggest that IDH is never present in primary GBM.
It does suggest that distinct genetic alterations may contribute to initiation and progression of gliomas. The presence of the IDH mutation in secondary GBM tumors suggests a different genetic pathway for GBM progression from a low grade tumor, compared to the genetic pathways leading to primary GBM initiation from normal cells.
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[each_answer] => A. the IDH mutation is exclusive to secondary GBM tumors and is never found in primary GBM tumors.
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[each_answer] => B. tumor grade has no impact on the prevalence of the IDH mutation in GBM tumors.
)
[2] => Array
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[each_answer] => C. distinct genetic alterations may contribute to initiation and progression of gliomas.
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[each_answer] => D. the probability of survival after 30 months is lower for secondary GBM patients.
)
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[quiz_unique_key] => 1403770772
[question] => Which equation best represents how the concentration of a substance like NADPH is determined spectrophotometrically?
(A is the absorbance, ε is the molar absorptivity, and L is the path length.)
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
Spectrophotometry is used to measure the concentration of a substance in a solution, to study the absorption or transmission of light by molecules, and to determine the presence of specific chemical compounds. The basic principle involves passing light through a sample and measuring how much of that light is absorbed or transmitted at different wavelengths.
When light is passed through a solution containing an analyte that absorbs that light, the absorbance will be proportional to the length of the path the light travels, the concentration of the analyte, and the molar absorptivity of the analyte.
The Beer-Lambert Law (A = ε⋅c⋅L) is therefore used to calculate the concentration of the analyte based on its absorbance. Here, ε is the molar absorptivity, c is the concentration, and L is the path length.
Rearranging the equation shows that the concentration equals the absorbance divided by the other variables: c = A / (ε⋅L) .
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[each_answer] => A. c = A⋅ε / L
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[each_answer] => B. c = A / (ε⋅L)
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[each_answer] => C. c = (ε⋅L) / A
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[each_answer] => D. c = A⋅L / ε
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Figure 1
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