Article

Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy

Department of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Journal of Neuro-Oncology (Impact Factor: 3.07). 03/2012; 107(1):197-205. DOI: 10.1007/s11060-011-0737-8
Source: PubMed

ABSTRACT

Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(−)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography–mass spectrometry (LC–MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC–MS (r
2 = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r
2
= 0.59; P = 0.026). In conclusion, water-suppressed proton (1H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.

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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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    • "The metabolites (molecular weight <1 kDa) can be detected in vitro by gas chromatography-mass spectrometry (GCMS), liquid chromatography-mass spectrometry (LCMS), and nuclear magnetic resonance (NMR) spectroscopy [11]. Magnetic resonance spectroscopy also enables in vivo assessment of metabolites (such as 2HG) in the setting of brain tumors [12]. NMR-based methods are less sensitive but more reproducible than LCMS for the quantitative assessment of metabolites. "
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    ABSTRACT: Paragangliomas (PGLs) are frequently associated with germline mutations in genes involved in energy metabolism. The purpose of the present study was to assess whether the tumor metabolomic profile of patients with hereditary and apparently sporadic PGLs enables the distinction of different subtypes of tumors. Twenty-eight unrelated patients with a histological diagnosis of PGLs were included in the present study. Twelve had germline mutations in SDHx genes (5 SDHB, 7 SDHD), 6 VHL, and 10 were apparently sporadic. Intact tumor samples from these patients (one per patient) were evaluated with (1)H high-resolution magic angle spinning (HRMAS) NMR spectroscopy. SDHx-related tumors were characterized by an increase in succinate levels in comparison to other tumor subtypes (p = 0.0001 vs VHL and p = 0.000003 vs apparently sporadic). Furthermore, we found significantly lower values of glutamate in SDHx-related tumors compared to other subtypes (p = 0.0007 vs VHL and p = 0.003 vs apparently sporadic). Moreover, SDHx-tumors also exhibited lower values of ATP/ADP/AMP (p = 0.01) compared to VHL. VHL tumors were found to have the highest values of glutathione (GSH) compared to other tumors. Based on 4 metabolites (succinate, glutamate, GSH, and ATP/ADP/AMP), tumors were accurately distinguished from the other ones on both 3- and 2-class PLS-DA models. The present study shows that HRMAS NMR spectroscopy is a very promising method for investigating the metabolomic profile of various PGLs. The present data suggest the existence of a specific succinate-glutamate hallmark of SDHx PGLs. The relevance of such a metabolomic hallmark is expected to be very useful in designing novel treatment options as well as improving the diagnosis and follow-up of these tumors, including metastatic ones.
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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.
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