Article
Identification of metabolomic phenotypes of malignancy in IDH-mutant gliomas
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Authors
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Franziska Loebel
- Department of Neurosurgery, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA; Brain Tumor Research Lab / MGH Cancer Center, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA; Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA
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Leo L. Cheng
- Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA; Department of Radiopathology, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA
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Emily A. Decelle
- Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA; Department of Radiopathology, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA
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Andrew S. Chi
- Brain Tumor Research Lab / MGH Cancer Center, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA
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Ovidiu C. Andronesi
- Martinos Center for Biomedical Imaging, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA
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Daniel P. Cahill
- Department of Neurosurgery, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA; Brain Tumor Research Lab / MGH Cancer Center, Massachusetts General Hospital / Harvard Medical School, Boston, MA, USA
| Published: | May 13, 2014 |
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Outline
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Objective: Recurrent mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) define a distinct subgroup of human gliomas, characterized by younger age, reduced rates of malignant progression and better prognosis, compared to IDH-wildtype tumors. While all IDH-mutant gliomas show a characteristic overproduction of 2-hydroxyglutarate (2HG), which can be detected by Magnetic Resonance Spectroscopy (MRS), little is known about additional molecular and metabolomic differences between more aggressive high-grade IDH-mutant tumors and more indolent low-grade cases. The present study aimed at identifying metabolomic predictors of malignancy in the subset of IDH-mutant gliomas, using ex-vivo High-Resolution Magic Angle Spinning (¹H HRMAS) MRS.
Method: Frozen tissue samples collected after surgical resection of 8 IDH-mutant low-grade gliomas (grade II) and 12 high-grade cases (grade III/IV) were subjected to ¹H HRMAS MRS using a 600MHz (14.1T) spectrometer. Conventional one-dimensional ¹H HRMAS MRS and two-dimensional correlation spectroscopy were performed to measure spectral intensities. Subsequently, the tissue samples were subjected to histopathological analysis and immunohistochemistry for confirmation of IDH-mutation. Spectroscopy data was processed using NUTS software. Spectral intensities were correlated with histopathologic information and compared between high- and low-grade groups.
Results: Investigation of the first five samples showed detectable 2HG-signals, confirming sensitivity of our method for IDH-mutation. We were additionally able to observe strong differences in spectral intensities, up to 80-fold, between high- and low-grade cases in 12 regions, corresponding to the metabolites glycerophosphocholine, lactate, phosphocholine and glutamate (elevated in high-grade cases), as well as GABA, choline, creatine and aspartate (decreased in high-grade gliomas).
Conclusions: Our results suggest that high-grade IDH-mutant gliomas show distinct metabolomic differences compared to low-grade cases. Further investigation of our larger cohort will prove useful for confirmation and statistical validation of these initial findings. ¹H HRMAS MRS has strong clinical applicability, yielding the potential to distinguish between aggressive and malignant IDH-mutant gliomas, which require immediate action, and indolent low-grade tumors. Ultimately, our method could provide utility in the management of IDH-mutant glioma patients, supporting strategic planning of surgical resection and follow-up treatment.
