Detection of 2-Hydroxyglutarate in IDH-Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Science translational medicine (Impact Factor: 15.84). 01/2012; 4(116):116ra4. DOI: 10.1126/scitranslmed.3002693
Source: PubMed


Mutations in the gene isocitrate dehydrogenase 1 (IDH1) are present in up to 86% of grade II and III gliomas and secondary glioblastoma. Arginine 132 (R132) mutations in the enzyme IDH1 result in excess production of the metabolite 2-hydroxyglutarate (2HG), which could be used as a biomarker for this subset of gliomas. Here, we use optimized in vivo spectral-editing and two-dimensional (2D) correlation magnetic resonance spectroscopy (MRS) methods to unambiguously detect 2HG noninvasively in glioma patients with IDH1 mutations. By comparison, fitting of conventional 1D MR spectra can provide false-positive readouts owing to spectral overlap of 2HG and chemically similar brain metabolites, such as glutamate and glutamine. 2HG was also detected using 2D high-resolution magic angle spinning MRS performed ex vivo on a separate set of glioma biopsy samples. 2HG detection by in vivo or ex vivo MRS enabled detailed molecular characterization of a clinically important subset of human gliomas. This has implications for diagnosis as well as monitoring of treatments targeting mutated IDH1.

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Available from: Grace Sooyeon Kim, Nov 05, 2015
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    • " of 2HG to a - ketoglutarate in the presence of the enzyme ( D ) 22 - hydroxyglutarate dehydrogenase and NAD 1 and detection of stoichiometrically generated NADH ( Balss et al . , 2012 ) . Recently , a promising nonin - vasive technique for 2HG level detection ex vivo by mag - netic resonance spectroscopy was developed by Choi et al . ( 2012 ) and Andronesi et al . ( 2012 ) . Results obtained with this new method correlated with MS analysis results with high reproducibility ( Choi et al . , 2012 ) . CONCLUSIONS Since the seminal study by Parsons et al . ( 2008 ) that first described IDH1 mutations in a group of glioblastomas , there has been considerable progress toward understand - ing the role of IDH m"
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    ABSTRACT: Over the past few years, new biomarkers have allowed a deeper insight into gliomagenesis and facilitated the identification of possible targets for glioma therapy. Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations have been shown to be promising biomarkers for monitoring disease prognosis and predicting the response to treatment. This review summarizes recent findings in this field. Web of Science, Science Direct, and PubMed online databases were used to search for publications investigating the role of IDH in glioma. References were identified by searching for the keywords "IDH1 or IDH2 and glioma and diagnostic or predictive or prognostic" in papers published from January, 2008, to April, 2014. Only papers in English were reviewed. Publications available only as an abstract were not included. IDH1/2 mutations are tightly associated with grade II and III gliomas and secondary glioblastomas, with better prognosis and production of a recently described oncometabolite, 2-hydroxyglutarate (2HG). Although the contradictory positive effect of IDH mutation on prognosis and negative role of 2HG in tumor transformation remain unresolved, the future direction of personalized treatment strategies targeted to glioma development is likely to focus on IDH1/2 mutations. © 2014 Wiley Periodicals, Inc.
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    • "Especially for glioblastoma, these findings have led to clinical relevance, since 60–80% of all astrocytomas, oligodendrogliomas, and oligoastrocytomas of WHO grade II and III harbor IDH1 mutations and are therefore regularly checked for D2HG as a marker for diagnostic and prognostic purposes (Hartmann et al., 2009). Furthermore, D2HG levels are measured in serum/plasma of AML (Pollyea et al., 2013) and in glioma patients using non-invasive proton magnetic resonance spectroscopy (MRS) (Andronesi et al., 2012;Choi et al., 2012;Elkhaled et al., 2012;Pope et al., 2012). Tumor-specific IDH1/2 mutations were further utilized as targets for chemotherapy and led to the development of specific small-molecule inhibitors with the aim of reducing D2HG levels and inhibiting tumorigenesis. "
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    ABSTRACT: The majority of cancers demonstrate various tumor-specific metabolic aberrations, such as increased glycolysis even under aerobic conditions (Warburg effect), whereas mitochondrial metabolic activity and their contribution to cellular energy production are restrained. One of the most important mechanisms for this metabolic switch is the alteration in the abundance, utilization, and localization of various mitochondrial substrates. Numerous lines of evidence connect disturbances in mitochondrial metabolic pathways with tumorigenesis and provide an intriguing rationale for utilizing mitochondria as targets for anticancer therapy.
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    • "Clinically, this mutation is associated with a more favorable prognosis, and it is more ubiquitously found early in the genesis of adult lower grade malignant gliomas and secondary glioblastoma (GBM) [7],[11],[12],[13]. The mutations have subsequently become important as diagnostic tools, in addition, because 2HG is visible by mass resonance spectroscopy (MRS) in patients [14],[15],[16], and an antibody against the most common mutation, R132H, has been developed that unequivocally recognizes individual tumor cells [17]. "
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    ABSTRACT: OLIGODENDROGLIOMA POSES A BIOLOGICAL CONUNDRUM FOR MALIGNANT ADULT HUMAN GLIOMAS: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP) positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H) and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.
    Full-text · Article · Aug 2013 · PLoS ONE
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