Detection of 2-Hydroxyglutarate in IDH-Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy
Science Translational Medicine • 11 Jan 2012 • Vol 4, Issue 116 • p. 116ra4 • DOI: 10.1126/scitranslmed.3002693
Spectroscopy Gets Inside Your Head
Gliomas are diffuse brain tumors that are difficult to diagnose, with outcomes that are nearly impossible to predict—unless you can sample the diseased tissue itself via biopsy. This invasive procedure is typically performed at the time of surgery, with results available only after several weeks. Normally, it is a good thing that people can’t “see” inside your head; but, for gliomas, Andronesi and coauthors have found it to be beneficial by noninvasively imaging the brain to identify a glioma gene mutation that is correlated with patient survival.
Mutations in the enzyme isocitrate dehydrogenase (IDH) lead to the accumulation of the metabolite 2-hydroxyglutarate (2HG). This mutation has been found in up to 86% of grade II to IV gliomas. Patients with IDH1 gene mutations have a greater 5-year survival rate than do patients with wild-type IDH1 gliomas, suggesting that such mutations could be used for prognosis. Andronesi et al. developed a strategy to detect IDH1 mutations in patients with glioma using magnetic resonance spectroscopy (MRS) imaging of 2HG. The similarity of 2HG to other metabolites, such as glutamate and glutamine, precludes detection with traditional one-dimensional spectroscopy; however, two-dimensional MRS allowed the authors to see the presence of 2HG in the brains of two glioma patients with IDH1 mutations, but not in healthy volunteers with wild-type IDH. The method was further validated ex vivo in tissue biopsies.
With these results and those in the companion study by Elkhaled et al. (also in this issue), the authors show that in vivo brain imaging for genotyping cancer patients is a possibility—one that would avoid invasive clinical procedures and help doctors not only predict cancer outcomes but also effectively treat tumors on the basis of grade and genetic makeup.
Abstract
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.
Get full access to this article
View all available purchase options and get full access to this article.
Already a Subscriber?Sign In
Supplementary Material
Summary
Materials and Methods
Fig. S1. Pulse sequence diagram for the 1D MEGA-LASER spectral editing experiment.
Fig. S2. Phantom experiments and simulations for 2D LASER-COSY and 1D LASER at 3 T.
Fig. S3. Optimization of the 1D MEGA-LASER spectral editing on phantoms at 3 T.
Fig. S4. 1D HR-MAS spectra recorded at 14 T and 3-kHz MAS on a biopsy sample from one patient with R132H IDH1 anaplastic astrocytoma.
Fig. S5. LCModel fitting of the 1D LASER spectrum from the R132C IDH1 anaplastic astrocytoma patient.
Fig. S6. LCModel fitting of the 1D LASER spectrum from a wild-type IDH1 primary glioblastoma patient.
Fig. S7. LCModel fitting of the 1D LASER spectrum from a wild-type IDH1 healthy volunteer.
Fig. S8. LCModel fitting of the 1D LASER spectrum from the tumor voxel of the R132H IDH1 secondary glioblastoma patient.
Fig. S9. LCModel fitting of the 1D LASER spectrum from the healthy side voxel of the R132H IDH1 secondary glioblastoma patient.
References
Resources
File (4-116ra4_sm.pdf)
References and Notes
1
Parsons D. W., Jones S., Zhang X., Lin J. C. H., Leary R. J., Angenendt P., Mankoo P., Carter H., Siu I. M., Gallia G. L., Olivi A., McLendon R., Rasheed B. A., Keir S., Nikolskaya T., Nikolsky Y., Busam D. A., Tekleab H., Diaz L. A., Hartigan J., Smith D. R., Strausberg R. L., Marie S. K. N., Shinjo S. M. O., Yan H., Riggins G. J., Bigner D. D., Karchin R., Papadopoulos N., Parmigiani G., Vogelstein B., Velculescu V. E., Kinzler K. W., An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
2
Cancer Genome Atlas Research Network, Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).
3
Yan H., Parsons D. W., Jin G., McLendon R., Rasheed B. A., Yuan W., Kos I., Batinic-Haberle I., Jones S., Riggins G. J., Friedman H., Friedman A., Reardon D., Herndon J., Kinzler K. W., Velculescu V. E., Vogelstein B., Bigner D. D., IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
4
Kloosterhof N. K., Bralten L. B. , Dubbink H. J., French P. J., van den Bent M. J., Isocitrate dehydrogenase-1 mutations: A fundamentally new understanding of diffuse glioma? Lancet Oncol. 12, 83–91 (2011).
5
Bleeker F. E., Atai N. A., Lamba S., Jonker A., Rijkeboer D., Bosch K. S., Tigchelaar W., Troost D., Vandertop W. P., Bardelli A., Van Noorden C. J. , The prognostic IDH1R132 mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol. 119, 487–494 (2010).
6
Mardis E. R., Ding L., Dooling D. J., Larson D. E., McLellan M. D., Chen K., Koboldt D. C., Fulton R. S., Delehaunty K. D., McGrath S. D., Fulton L. A., Locke D. P., Magrini V. J., Abbott R. M., Vickery T. L., Reed J. S., Robinson J. S., Wylie T., Smith S. M., Carmichael L., Eldred J. M., Harris C. C., Walker J., Peck J. B., Du F., Dukes A. F., Sanderson G. E., Brummett A. M., Clark E., McMichael J. F., Meyer R. J., Schindler J. K., Pohl C. S., Wallis J. W., Shi X., Lin L., Schmidt H., Tang Y., Haipek C., Wiechert M. E., Ivy J. V., Kalicki J., Elliott G., Ries R. E., Payton J. E., Westervelt P., Tomasson M. H., Watson M. A., Baty J., Heath S., Shannon W. D., Nagarajan R., Link D. C., Walter M. J., Graubert T. A., DiPersio J. F., Wilson R. K., Ley T. J., Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).
7
Dang L., White D. W., Gross S., Bennett B. D., Bittinger M. A., Driggers E. M., Fantin V. R., Jang H. G., Jin S., Keenan M. C., Marks K. M., Prins R. M., Ward P. S., Yen K. E., Liau L. M., Rabinowitz J. D., Cantley L. C., Thompson C. B., Vander Heiden M. G., Su S. M., Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).
8
Yen K. E., Bittinger M. A., Su S. M., Fantin V. R., Cancer-associated IDH mutations: Biomarker and therapeutic opportunities. Oncogene 29, 6409–6417 (2010).
9
Reitman Z. J., Jin G., Karoly E. D., Spasojevic I., Yang J., Kinzler K. W., He Y., Bigner D. D., Vogelstein B., Yan H., Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc. Natl. Acad. Sci. U.S.A. 108, 3270–3275 (2011).
10
Sener R. N., L-2 hydroxyglutaric aciduria: Proton magnetic resonance spectroscopy and diffusion magnetic resonance imaging findings. J. Comput. Assist. Tomogr. 27, 38–43 (2003).
11
Goffette S. M., Duprez T. P., Nassogne M. C. , Vincent M. F. , Jakobs C., Sindic C. J., l-2-Hydroxyglutaric aciduria: Clinical, genetic, and brain MRI characteristics in two adult sisters. Eur. J. Neurol. 13, 499–504 (2006).
12
Provencher S. W., Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn. Reson. Med. 30, 672–679 (1993).
13
Naressi A., Couturier C., Devos J. M., Janssen M., Mangeat C., de Beer R., Graveron-Demilly D., Java-based graphical user interface for the MRUI quantitation package. MAGMA 12, 141–152 (2001).
14
Mescher M., Merkle H., Kirsch J., Garwood M., Gruetter R., Simultaneous in vivo spectral editing and water suppression. NMR Biomed. 11, 266–272 (1998).
15
Ernst R. R., 2-Dimensional spectroscopy. Chimia 29, 179–183 (1975).
16
Andronesi O. C., Ramadan S., Mountford C. E., Sorensen A. G., Low-power adiabatic sequences for in vivo localized two-dimensional chemical shift correlated MR spectroscopy. Magn. Reson. Med. 64, 1542–1556 (2010).
17
Bal D., Gryff-Keller A., 1H and 13C NMR study of 2-hydroxyglutaric acid and its lactone. Magn. Reson. Chem. 40, 533–536 (2002).
18
Govindaraju V., Young K., Maudsley A. A., Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed. 13, 129–153 (2000).
19
Opstad K. S., Bell B. A., Griffiths J. R., Howe F. A., Toward accurate quantification of metabolites, lipids, and macromolecules in HRMAS spectra of human brain tumor biopsies using LCModel. Magn. Reson. Med. 60, 1237–1242 (2008).
20
Ramadan S., Andronesi O. C., Stanwell P., Lin A. P., Sorensen A. G., Mountford C. E., Use of in vivo two-dimensional MR spectroscopy to compare the biochemistry of the human brain to that of glioblastoma. Radiology 259, 540–549 (2011).
21
Usenius J. P., Vainio P., Hernesniemi J., Kauppinen R. A., Choline-containing compounds in human astrocytomas studied by 1H NMR spectroscopy in vivo and in vitro. J. Neurochem. 63, 1538–1543 (1994).
22
Sabatier J., Gilard V., Malet-Martino M., Ranjeva J. P., Terral C., Breil S., Delisle M. B., Manelfe C., Tremoulet M., Berry I., Characterization of choline compounds with in vitro 1H magnetic resonance spectroscopy for the discrimination of primary brain tumors. Invest. Radiol. 34, 230–235 (1999).
23
Righi V., Roda J. M., Paz J., Mucci A., Tugnoli V., Rodriguez-Tarduchy G., Barrios L., Schenetti L., Cerdán S., García-Martín M. L., 1H HR-MAS and genomic analysis of human tumor biopsies discriminate between high and low grade astrocytomas. NMR Biomed. 22, 629–637 (2009).
24
Beckonert O., Coen M., Keun H. C., Wang Y., Ebbels T. M. D., Holmes E., Lindon J. C., Nicholson J. K., High-resolution magic-angle-spinning NMR spectroscopy for metabolic profiling of intact tissues. Nat. Protoc. 5, 1019–1032 (2010).
25
Near J., Simpson R., Cowen P., Jezzard P., Efficient γ-aminobutyric acid editing at 3T without macromolecule contamination: MEGA-SPECIAL. NMR Biomed. 34, 1277–1285 10.1002/nbm.1688 (2011).
26
Kunz M., Thon N., Eigenbrod S., Hartmann C., Egensperger R., Herms J., Geisler J., la Fougere C., Lutz J., Linn J., Kreth S., von Deimling A., Tonn J. C., Kretzschmar H. A., Pöpperl G., Kreth F. W., Hot spots in dynamic 18FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas. Neuro Oncol. 13, 307–316 (2011).
27
Andronesi O. C., Gagoski B. A., Adalsteinsson E., Sorensen A. G., Correlation chemical shift imaging with low-power adiabatic pulses and constant-density spiral trajectories. NMR Biomed. 10.1002/nbm.1730 (2011). http://onlinelibrary.wiley.com/doi/10.1002/nbm.1730/abstract
28
Zhu H., Edden R. A., Ouwerkerk R., Barker P. B., High resolution spectroscopic imaging of GABA at 3 Tesla. Magn. Reson. Med. 65, 603–609 (2011).
29
Xu W., Yang H., Liu Y., Yang Y., Wang P., Kim S. H., Ito S., Yang C., Wang P., Xiao M. T., Liu L. X., Jiang W. Q., Liu J., Zhang J. Y., Wang B., Frye S., Zhang Y., Xu Y. H., Lei Q. Y., Guan K. L., Zhao S. M., Xiong Y., Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).
30
Williams S. C., Karajannis M. A., Chiriboga L., Golfinos J. G., von Deimling A., Zagzag D., R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1α upregulation in adult glioma. Acta Neuropathol. 121, 279–281 (2011).
31
Andronesi O. C., Ramadan S., Ratai E. M., Jennings D., Mountford C. E., Sorensen A. G., Spectroscopic imaging with improved gradient modulated constant adiabaticity pulses on high-field clinical scanners. J. Magn. Reson. 203, 283–293 (2010).
32
Ogg R. J., Kingsley P. B., Taylor J. S., WET, a T1- and B1-insensitive water-suppression method for in vivo localized 1H NMR spectroscopy. J. Magn. Reson. B 104, 1–10 (1994).
33
Gruetter R., Tkác I., Field mapping without reference scan using asymmetric echo-planar techniques. Magn. Reson. Med. 43, 319–323 (2000).
34
van der Kouwe A. J. , Benner T., Salat D. H., Fischl B., Brain morphometry with multiecho MPRAGE. Neuroimage 40, 559–569 (2008).
35
Lin Y. Y., Hodgkinson P., Ernst M., Pines A., A novel detection–estimation scheme for noisy NMR signals: Applications to delayed acquisition data. J. Magn. Reson. 128, 30–41 (1997).
36
Martínez-Bisbal M. C., Martí-Bonmatí L., Piquer J., Revert A., Ferrer P., Llácer J. L., Piotto M., Assemat O., Celda B., 1H and 13C HR-MAS spectroscopy of intact biopsy samples ex vivo and in vivo 1H MRS study of human high grade gliomas. NMR Biomed. 17, 191–205 (2004).
37
Thomas M. A., Hattori N., Umeda M., Sawada T., Naruse S., Evaluation of two-dimensional L-COSY and JPRESS using a 3 T MRI scanner: From phantoms to human brain in vivo. NMR Biomed. 16, 245–251 (2003).
Information & Authors
Information
Published In
Science Translational Medicine
Volume 4 | Issue 116
January 2012
January 2012
Copyright
Copyright © 2012, American Association for the Advancement of Science.
Submission history
Received: 23 May 2011
Accepted: 23 November 2011
Acknowledgments
We would like to acknowledge J. A. Iafrate and D. N. Louis from the Department of Pathology of Massachusetts General Hospital for assistance with SNaPshot analysis for IDH mutation and useful comments on our results. We also acknowledge P. M. Black from the Department of Neurosurgery of Brigham and Women’s Hospital for access to biopsies that were analyzed by ex vivo HR-MAS spectroscopy. We thank M. Malgorzata and M. Garwood from Center for Magnetic Resonance Research at University of Minnesota for help with LCModel basis set for LASER excitation. Funding: This work was funded by grants from NIH (R01 1200-206456, S10RR013026, S10RR021110, and S10RR023401). O.C.A. was also supported by a KL2 Medical Research Investigator Training (MeRIT) award from Harvard Catalyst, The Harvard Clinical and Translational Science Center (NIH Award #KL2 RR 025757). Author contributions: O.C.A. provided conceptual design, obtained measurements, analyzed the data, and drafted the manuscript. G.S.K. obtained experimental measurements. E.G. and T.B. recruited patients and provided clinical guidance and manuscript review. A.A.T. provided support for biopsy measurements and manuscript review. V.R.F. performed LC-MS measurements, literature review, and manuscript editing. M.G.V.H. provided expertise on IDH1 mutations and 2HG, literature review, and manuscript editing. A.G.S. initiated the project, funding support, and manuscript review. Competing interests: The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the NIH. O.C.A. and A.G.S. have applied for a patent for the 2D COSY-LASER method that is used in the paper, U.S. Patent Application Serial No. 13/237,799.
Authors
Metrics & Citations
Metrics
Article Usage
Altmetrics
Citations
Export citation
Select the format you want to export the citation of this publication.
Cited by
- Reverse Engineering Glioma Radiomics to Conventional Neuroimaging, Neurologia medico-chirurgica, (2021).https://doi.org/10.2176/nmc.ra.2021-0133
- Shimming—the forgotten child of in-vivo MR?, Magnetic Resonance Materials in Physics, Biology and Medicine, 34, 2, (179-181), (2021).https://doi.org/10.1007/s10334-021-00920-5
- Spectral fitting strategy to overcome the overlap between 2‐hydroxyglutarate and lipid resonances at 2.25 ppm, Magnetic Resonance in Medicine, 86, 4, (1818-1828), (2021).https://doi.org/10.1002/mrm.28829
- Quantitative Analysis of Oncometabolite 2-Hydroxyglutarate, Cancer Metabolomics, (161-172), (2021).https://doi.org/10.1007/978-3-030-51652-9_11
- IDH Inhibitors and Beyond: The Cornerstone of Targeted Glioma Treatment, Molecular Diagnosis & Therapy, 25, 4, (457-473), (2021).https://doi.org/10.1007/s40291-021-00537-3
- Imaging and treatment of brain tumors through molecular targeting: Recent clinical advances, European Journal of Radiology, 142, (109842), (2021).https://doi.org/10.1016/j.ejrad.2021.109842
- Isocitrate Dehydrogenase Mutant Grade II and III Glial Neoplasms, Hematology/Oncology Clinics of North America, (2021).https://doi.org/10.1016/j.hoc.2021.08.008
- Spectroscopic MRI for Brain Tumor Imaging, Molecular Imaging, (1077-1090), (2021).https://doi.org/10.1016/B978-0-12-816386-3.00079-X
- Novel Magnetic Resonance Imaging and Positron Emission Tomography in the RT Planning and Assessment of Response of Malignant Gliomas, Molecular Imaging, (1031-1048), (2021).https://doi.org/10.1016/B978-0-12-816386-3.00078-8
- Magnetic Resonance Metabolic Imaging of Glioma, Science Translational Medicine, 4, 116, (116ps1-116ps1), (2021)./doi/10.1126/scitranslmed.3003591
- See more
Loading...
View Options
Get Access
Log in to view the full text
AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.
- Become a AAAS Member
- Activate your AAAS ID
- Purchase Access to Other Journals in the Science Family
- Account Help
Log in via OpenAthens.
Log in via Shibboleth.
More options
Register for free to read this article
As a service to the community, this article is available for free. Login or register for free to read this article.
View options
PDF format
Download this article as a PDF file
Download PDF