Daniel Connors

Introduction. Glioblastoma is an aggressive astrocyte-derived brain cancer with a poor prognosis. Survival in glioblastoma patients is typically prolonged for only a few months with intervention.¹ In adult glioblastoma patients, mutations in IDH1/2 genes presage a better overall survival.⁵ IDH1mt patients have been shown to have longer survival times, by up to two years, due to increased NADPH oxidation. NADPH is an intracellular reducing agent that is crucial for the reduction of ROS, catalase, thioredoxin, and Cytochrome P450.⁶ This review aims to highlight the most noteworthy recent research demonstrating the functional significance of IDH mutations in glioblastoma. Methods. A systematic review of current relevant literature. We searched medical research databases for articles published between 2017-2022. Our search terms included glioblastoma, IDH1/2, and IDH mutations. Articles were selected for review if their results offered insight into the function of IDH in glioblastoma biology. Results. IDH-1 MT mice demonstrated decreased p-ATM vs IDH-1 WTs.⁷ Tumor volume was decreased in mutants with TMZ delivery.⁷ Mutants have enhanced PYCR1 mediated proline production.⁸ Increased proline production bypassed complex I (ETC) by oxidizing NADH.⁸ Mutants maintain CAC functioning in limited oxygen environment.⁸ PYCR1 intensity correlated to 2-HG levels.⁸ WT Gliomas have higher levels of GSH, taurine, ascorbic acid, and nucleotide levels than MTs.⁹ WTs have an increase in lactate, glutamate, glutamine, and citrate compared to mutants.⁹ Mutants exhibit higher levels of 2-HG.⁹ Mutants demonstrate a higher level of NAA.⁹ Differences in FAP uptake were observed between graded gliomas. Tracer uptake PET imaging used to identify grade II glioma, III glioma, and GBM. NTRS have been shown to be corollary to Glioma grade. NTRS scores are higher in the wild type than in mutants.¹¹ This prognostic analysis demonstrates the gene expression differences that mutants exhibit. Conclusions. IDH-MT synthesize 2-HG which acts to decrease DNA methylation. Abnormal DNA methylation is known to increase activation of cancer promoting genes. IDH mutations in GBM have conversely been shown to increase the sensitization of GBM tumor to radiation therapy. Mutants show modulated ATM signaling that connotes susceptibility to chemotherapy. Elevated proline production in IDH1 mutants uncouples the electron transport chain from the citric acid cycle and allows the production of anabolic precursors in anoxic environments.⁸ Lower levels of these molecules in mutant cells correlates with the notion that mutants are more susceptible to cell damaging events. Mutation status is reflected in PET imaging. Monitoring tumor progression with tracer implemented PET imaging offers a novel tool for monitoring glioma transformation. Low expression of NTRS associated nuclear transport genes between IDH1/2 MT/WT GBMs offers insight into the underlying mechanism by which IDH mutations allow for increased survival times in patients and offers a possible prognostic marker for glioma grades when combined with IDH mutation. Highlighted signaling pathways and metabolic changes unique to mutant IDH GBM provide a groundwork for future therapy research.

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