2-hydroxyglutarate Detection by Magnetic Resonance Spectroscopy in IDH-mutated Patients with Gliomas

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2012 Jan 28

PMID 22281806

Citations 415

Authors

Changho Choi

Sandeep K Ganji

Ralph J DeBerardinis

Kimmo J Hatanpaa

Dinesh Rakheja

Zoltan Kovacs

Xiao-Li Yang

Tomoyuki Mashimo

Jack M Raisanen

Isaac Marin-Valencia

Juan M Pascual

Christopher J Madden

Bruce E Mickey

Craig R Malloy

Robert M Bachoo

Elizabeth A Maher

Affiliations

Soon will be listed here.

Abstract

Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) have been shown to be present in most World Health Organization grade 2 and grade 3 gliomas in adults. These mutations are associated with the accumulation of 2-hydroxyglutarate (2HG) in the tumor. Here we report the noninvasive detection of 2HG by proton magnetic resonance spectroscopy (MRS). We developed and optimized the pulse sequence with numerical and phantom analyses for 2HG detection, and we estimated the concentrations of 2HG using spectral fitting in the tumors of 30 subjects. Detection of 2HG correlated with mutations in IDH1 or IDH2 and with increased levels of D-2HG by mass spectrometry of the resected tumors. Noninvasive detection of 2HG may prove to be a valuable diagnostic and prognostic biomarker.

Citing Articles

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PMID: 40087637 DOI: 10.1186/s12885-025-13877-8.

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References

Maher E, Brennan C, Wen P, Durso L, Ligon K, Richardson A . Marked genomic differences characterize primary and secondary glioblastoma subtypes and identify two distinct molecular and clinical secondary glioblastoma entities. Cancer Res. 2006; 66(23):11502-13. DOI: 10.1158/0008-5472.CAN-06-2072. View

Ganji S, Banerjee A, Patel A, Zhao Y, Dimitrov I, Browning J . T2 measurement of J-coupled metabolites in the human brain at 3T. NMR Biomed. 2011; 25(4):523-9. PMC: 3852663. DOI: 10.1002/nbm.1767. View

Goffette S, Duprez T, Nassogne M, Vincent M, Jakobs C, Sindic C . L-2-Hydroxyglutaric aciduria: clinical, genetic, and brain MRI characteristics in two adult sisters. Eur J Neurol. 2006; 13(5):499-504. DOI: 10.1111/j.1468-1331.2006.01282.x. View

Govindaraju V, Young K, Maudsley A . Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed. 2000; 13(3):129-53. DOI: 10.1002/1099-1492(200005)13:3<129::aid-nbm619>3.0.co;2-v. View

McLean L, Roscoe J, Jorgensen N, Gorin F, Cala P . Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. Am J Physiol Cell Physiol. 2001; 278(4):C676-88. DOI: 10.1152/ajpcell.2000.278.4.C676. View

Norton W, Poduslo S, Suzuki K . Subacute sclerosing leukoencephalitis. II. Chemical studies including abnormal myelin and an abnormal ganglioside pattern. J Neuropathol Exp Neurol. 1966; 25(4):582-97. DOI: 10.1097/00005072-196610000-00006. View

Parsons D, Jones S, Zhang X, Cheng-Ho Lin J, Leary R, Angenendt P . An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321(5897):1807-12. PMC: 2820389. DOI: 10.1126/science.1164382. View

Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A . Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008; 116(6):597-602. DOI: 10.1007/s00401-008-0455-2. View

Dang L, White D, Gross S, Bennett B, Bittinger M, Driggers E . Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009; 462(7274):739-44. PMC: 2818760. DOI: 10.1038/nature08617. View

10.

Mlynarik V, Gruber S, Moser E . Proton T (1) and T (2) relaxation times of human brain metabolites at 3 Tesla. NMR Biomed. 2001; 14(5):325-31. DOI: 10.1002/nbm.713. View

11.

Provencher S . Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993; 30(6):672-9. DOI: 10.1002/mrm.1910300604. View

12.

Choi C, Ganji S, DeBerardinis R, Dimitrov I, Pascual J, Bachoo R . Measurement of glycine in the human brain in vivo by 1H-MRS at 3 T: application in brain tumors. Magn Reson Med. 2011; 66(3):609-18. PMC: 3139742. DOI: 10.1002/mrm.22857. View

13.

Rakheja D, Mitui M, Boriack R, DeBerardinis R . Isocitrate dehydrogenase 1/2 mutational analyses and 2-hydroxyglutarate measurements in Wilms tumors. Pediatr Blood Cancer. 2011; 56(3):379-83. DOI: 10.1002/pbc.22697. View

14.

Yan H, Parsons D, Jin G, McLendon R, Rasheed B, Yuan W . IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009; 360(8):765-73. PMC: 2820383. DOI: 10.1056/NEJMoa0808710. View

15.

Figueroa M, Abdel-Wahab O, Lu C, Ward P, Patel J, Shih A . Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010; 18(6):553-67. PMC: 4105845. DOI: 10.1016/j.ccr.2010.11.015. View

16.

Thompson R, Allen P . Sources of variability in the response of coupled spins to the PRESS sequence and their potential impact on metabolite quantification. Magn Reson Med. 1999; 41(6):1162-9. DOI: 10.1002/(sici)1522-2594(199906)41:6<1162::aid-mrm12>3.0.co;2-n. View

17.

Nuri Sener R . L-2 hydroxyglutaric aciduria: proton magnetic resonance spectroscopy and diffusion magnetic resonance imaging findings. J Comput Assist Tomogr. 2003; 27(1):38-43. DOI: 10.1097/00004728-200301000-00008. View

18.

von Deimling A, Korshunov A, Hartmann C . The next generation of glioma biomarkers: MGMT methylation, BRAF fusions and IDH1 mutations. Brain Pathol. 2010; 21(1):74-87. PMC: 8094257. DOI: 10.1111/j.1750-3639.2010.00454.x. View

19.

Rakheja D, Boriack R, Mitui M, Khokhar S, Holt S, Kapur P . Papillary thyroid carcinoma shows elevated levels of 2-hydroxyglutarate. Tumour Biol. 2010; 32(2):325-33. DOI: 10.1007/s13277-010-0125-6. View

20.

Choi C, Dimitrov I, Douglas D, Patel A, Kaiser L, Amezcua C . Improvement of resolution for brain coupled metabolites by optimized (1)H MRS at 7T. NMR Biomed. 2010; 23(9):1044-52. DOI: 10.1002/nbm.1529. View