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

被引：317

作者：

Andronesi, Ovidiu C. ^{[1
]}

Kim, Grace S. ^{[1
]}

Gerstner, Elizabeth ^{[2
]}

Batchelor, Tracy ^{[2
]}

Tzika, Aria A. ^{[1
,3
,7
]}

Fantin, Valeria R. ^{[4
]}

Vander Heiden, Matthew G. ^{[5
,6
]}

Sorensen, A. Gregory ^{[1
]}

机构：

[1] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging,Sch Med, Boston, MA 02114 USA

[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pappas Ctr Neurooncol, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Dept Surg, NMR Surg Lab, Boston, MA 02114 USA

[4] Agios Pharmaceut, Cambridge, MA 02139 USA

[5] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[6] Dana Farber Canc Inst, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Shriners Burn Inst, Boston, MA 02114 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2012年 / 4卷 / 116期

关键词：

H-1-NMR SPECTROSCOPY; WATER-SUPPRESSION; GENOMIC ANALYSIS; HR-MAS; MUTATIONS; H-1; GLIOBLASTOMA; ASTROCYTOMAS; METABOLITES; ACIDURIA;

D O I：

10.1126/scitranslmed.3002693

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：11

共 40 条

[1]

ANDRONESI OC, 2011, NMR BIOMED, DOI DOI 10.1002/NBM.1730

[2] Low-Power Adiabatic Sequences for In Vivo Localized Two-Dimensional Chemical Shift Correlated MR Spectroscopy [J].

Andronesi, Ovidiu C. ;

Ramadan, Saadallah ;

Mountford, Carolyn E. ;

Sorensen, A. Gregory .

MAGNETIC RESONANCE IN MEDICINE, 2010, 64 (06) :1542-1556

[3] Spectroscopic imaging with improved gradient modulated constant adiabaticity pulses on high-field clinical scanners [J].

Andronesi, Ovidiu C. ;

Ramadan, Saadallah ;

Ratai, Eva-Maria ;

Jennings, Dominique ;

Mountford, Carolyn E. ;

Sorensen, A. Gregory .

JOURNAL OF MAGNETIC RESONANCE, 2010, 203 (02) :283-293

[4] 1H and 13C NMR study of 2-hydroxyglutaric acid and its lactone [J].

Bal, D ;

Gryff-Keller, A .

MAGNETIC RESONANCE IN CHEMISTRY, 2002, 40 (08) :533-536

[5] High-resolution magic-angle-spinning NMR spectroscopy for metabolic profiling of intact tissues [J].

Beckonert, Olaf ;

Coen, Muireann ;

Keun, Hector C. ;

Wang, Yulan ;

Ebbels, Timothy M. D. ;

Holmes, Elaine ;

Lindon, John C. ;

Nicholson, Jeremy K. .

NATURE PROTOCOLS, 2010, 5 (06) :1019-1032

[6] The prognostic IDH1 R132 mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma [J].

Bleeker, Fonnet E. ;

Atai, Nadia A. ;

Lamba, Simona ;

Jonker, Ard ;

Rijkeboer, Denise ;

Bosch, Klazien S. ;

Tigchelaar, Wikky ;

Troost, Dirk ;

Vandertop, W. Peter ;

Bardelli, Alberto ;

Van Noorden, Cornelis J. F. .

ACTA NEUROPATHOLOGICA, 2010, 119 (04) :487-494

[7] Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].

Chin, L. ;

Meyerson, M. ;

Aldape, K. ;

Bigner, D. ;

Mikkelsen, T. ;

VandenBerg, S. ;

Kahn, A. ;

Penny, R. ;

Ferguson, M. L. ;

Gerhard, D. S. ;

Getz, G. ;

Brennan, C. ;

Taylor, B. S. ;

Winckler, W. ;

Park, P. ;

Ladanyi, M. ;

Hoadley, K. A. ;

Verhaak, R. G. W. ;

Hayes, D. N. ;

Spellman, Paul T. ;

Absher, D. ;

Weir, B. A. ;

Ding, L. ;

Wheeler, D. ;

Lawrence, M. S. ;

Cibulskis, K. ;

Mardis, E. ;

Zhang, Jinghui ;

Wilson, R. K. ;

Donehower, L. ;

Wheeler, D. A. ;

Purdom, E. ;

Wallis, J. ;

Laird, P. W. ;

Herman, J. G. ;

Schuebel, K. E. ;

Weisenberger, D. J. ;

Baylin, S. B. ;

Schultz, N. ;

Yao, Jun ;

Wiedemeyer, R. ;

Weinstein, J. ;

Sander, C. ;

Gibbs, R. A. ;

Gray, J. ;

Kucherlapati, R. ;

Lander, E. S. ;

Myers, R. M. ;

Perou, C. M. ;

McLendon, Roger .

NATURE, 2008, 455 (7216) :1061-1068

[8] Cancer-associated IDH1 mutations produce 2-hydroxyglutarate [J].

Dang, Lenny ;

White, David W. ;

Gross, Stefan ;

Bennett, Bryson D. ;

Bittinger, Mark A. ;

Driggers, Edward M. ;

Fantin, Valeria R. ;

Jang, Hyun Gyung ;

Jin, Shengfang ;

Keenan, Marie C. ;

Marks, Kevin M. ;

Prins, Robert M. ;

Ward, Patrick S. ;

Yen, Katharine E. ;

Liau, Linda M. ;

Rabinowitz, Joshua D. ;

Cantley, Lewis C. ;

Thompson, Craig B. ;

Heiden, Matthew G. Vander ;

Su, Shinsan M. .

NATURE, 2009, 462 (7274) :739-U52

[9]

ERNST RR, 1975, CHIMIA, V29, P179

[10] L-2-hydroxyglutaric aciduria: clinical, genetic, and brain MRI characteristics in two adult sisters [J].

Goffette, S. M. ;

Duprez, T. P. ;

Nassogne, M. -C. L. ;

Vincent, M. -F. A. ;

Jakobs, C. ;

Sindic, C. J. .

EUROPEAN JOURNAL OF NEUROLOGY, 2006, 13 (05) :499-504

← 1 2 3 4 →