Detection of “oncometabolite” 2-hydroxyglutarate by magnetic resonance analysis as a biomarker of IDH1/2 mutations in glioma
- 1k Downloads
Somatic mutations in isocitrate dehydrogenase (IDH)1 and 2 have been identified in a subset of gliomas, rendering these tumors with elevated levels of “oncometabolite,” D-2-hydroxyglutarate (2HG). Herein, we report that 2HG can be precisely detected by magnetic resonance (MR) in human glioma specimens and used as a reliable biomarker to identify this subset of tumors. Specifically, we developed a two-dimensional correlation spectroscopy resonance method to reveal the distinctive cross-peak pattern of 2HG in the complex metabolite nuclear MR spectra of brain tumor tissues. This study demonstrates the feasibility, specificity, and selectivity of using MR detection and quantification of 2HG for the diagnosis and classification of IDH1/2 mutation-positive brain tumors. It further opens up the possibility of developing analogous non-invasive MR-based imaging and spectroscopy studies directly in humans in the neuro-oncology clinic.
KeywordsCancer 2-Hydroxyglutarate Isocitrate dehydrogenase Nuclear magnetic resonance Biomarker
We thank Dr. Jeffrey Olson for the provision of brain tumor samples, Drs. Daniel Brat and Steven Hunter for neuropathological diagnosis, and Narra Sarojini Devi and Zhaobin Zhang for banking brain tumor tissue samples. We also thank the Winship Cancer Institute Tissue Procurement and Pathology core for tissue sectioning and immunohistochemistry services.
All authors concur with the content of the manuscript and assert that this report is not under consideration for publication elsewhere. No conflict of interest is noted.
This work was supported in part by NIH grants R01 CA86335 and CA116804 (to EGVM), R21AG032104-01A1 and P50CA128301-020003 (to HM), P30 CA138292 (to the Emory Winship Cancer Institute), NINDS Training Grant 2T32NS007480-11 (to JK and Allan I. Levey), a joint Translational Research Pilot Grant from the Winship Cancer Institute and the Atlanta Clinical & Translational Science Instite (ACTSI, UL1RR025008; to HM and EGVM), the Brain Tumor Funders Collaborative (to EGVM), and the Georgia Cancer Coalition (to JK and EGVM).
- 12.Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110PubMedCrossRefGoogle Scholar
- 14.Morvan D, Demidem A, Papon J, De Latour M, Madelmont JC (2002) Melanoma tumors acquire a new phospholipid metabolism phenotype under cystemustine as revealed by high-resolution magic angle spinning proton nuclear magnetic resonance spectroscopy of intact tumor samples. Cancer Res 62:1890–1897PubMedGoogle Scholar
- 17.Shi C, Wang X, Wu S, Zhu Y, Chung LW, Mao H (2008) HRMAS 1H-NMR measured changes of the metabolite profile as mesenchymal stem cells differentiate to targeted fat cells in vitro: implications for non-invasive monitoring of stem cell differentiation in vivo. J Tissue Eng Regen Med 2:482–490PubMedCrossRefGoogle Scholar
- 18.Rong Y, Belozerov VE, Tucker-Burden C, Chen G, Durden DL, Olson JJ, Van Meir EG, Mackman N, Brat DJ (2009) Epidermal growth factor receptor and PTEN modulate tissue factor expression in glioblastoma through JunD/activator protein-1 transcriptional activity. Cancer Res 69:2540–2549PubMedCrossRefGoogle Scholar
- 24.Pope WB, Prins RM, Albert Thomas M, Nagarajan R, Yen KE, Bittinger MA, Salamon N, Chou AP, Yong WH, Soto H et al (2012) Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy. J Neurooncol 107:197–205PubMedCrossRefGoogle Scholar