Studying the Biology of IDH-mutant Gliomas Via Longitudinal Observation of 2-hydroxyglutarate (2-HG) Using MR Spectroscopy

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Background: Glioma is the most common malignant brain tumor. Genes coding for isocitrate dehydrogenase (IDH), a metabolic enzyme, are frequently mutated in gliomas, particularly lower-grade gliomas (LGGs). IDH mutation causes a unique tumor biology, including the accumulation of 2-hydroxyglutarate (...

Background: Glioma is the most common malignant brain tumor. Genes coding for isocitrate dehydrogenase (IDH), a metabolic enzyme, are frequently mutated in gliomas, particularly lower-grade gliomas (LGGs). IDH mutation causes a unique tumor biology, including the accumulation of 2-hydroxyglutarate (2-HG), an oncometabolite, which in turn causes genomic hypermethylation and tumorigenesis. Despite having a better prognosis compared to their IDH WT counterparts, IDH-mutant LGGs undergo a slow but unremitting higher-grade transformation (HT) and eventually become high grade gliomas (HGGs). A subset of patients with transformed HGGs develop a hypermutator phenotype (HMP), possibly related to previous treatment with alkylating agents and radiotherapy. The timeline for the development of HT and HMP is unpredictable and there is no known way to prevent them from happening, largely due to a lack of understanding their biological mechanisms and lack of a non-invasive approach for potential early detection. Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-HG in a tumor harboring IDH mutation. There has been an increased interest in using quantitative 2-HG by MRS as a biomarker for IDH-mutant gliomas. This clinical study will allow a longitudinal monitoring of quantitative 2-HG by MRS in patients with IDH-mutant gliomas. We hypothesize that a significant increase in 2HG level is correlated with HT and/or HMP. The change in 2-HG level in conjunction with evaluation of tumor cellularity and other metabolite markers such as choline, creatinine and N-acetyl aspartate (NAA) will likely to provide insights into metabolic alterations that may correlate with HT/HMP and potentially provide the predictive biomarker for early detection of HT. Objective: -To monitor the quantitative levels of 2-hydroxyglutarate (2-HG) longitudinally in patients with IDH-mutant gliomas via proton magnetic resonance spectroscopy (1H-MRS). Eligibility: IDH 1 or 2 mutation confirmed by DNA sequencing. Age greater than or equal to18 years, KPS greater than or equal to 60% Design: This is prospective observational study. We will recruit at least 250 eligible patients in the next 5 years. The relationship between the occurrence of HT and the changes in 2-HG level using the proportional hazard model.

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