Selective detection of the D-enantiomer of 2-hydroxyglutarate in the CSF of glioma patients with mutated isocitrate dehydrogenase

Juliya Kalinina; Jun Ahn; Narra S. Devi; Liya Wang; Yuancheng Li; Jeffrey J. Olson; Michael Glantz; Thomas Smith; Ella L. Kim; Alf Giese; Randy L. Jensen; Clark C. Chen; Bob S. Carter; Hui Mao; Miao He; Erwin G. Van Meir

doi:10.1158/1078-0432.CCR-15-2965

Selective detection of the D-enantiomer of 2-hydroxyglutarate in the CSF of glioma patients with mutated isocitrate dehydrogenase

Juliya Kalinina, Jun Ahn, Narra S. Devi, Liya Wang, Yuancheng Li, Jeffrey J. Olson, Michael Glantz, Thomas Smith, Ella L. Kim, Alf Giese, Randy L. Jensen, Clark C. Chen, Bob S. Carter, Hui Mao, Miao He, Erwin G. Van Meir

Neurosurgery

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Purpose: Elevation in D-2-Hydroxyglutarate (D-2HG) has recently emerged as a mandatory byproduct of mutated Isocitrate Dehydrogenase (IDH) genes 1 and 2 in glioma patients. The goal of the present study was to demonstrate the feasibility of detection of elevated levels of D-2HG in the cerebrospinal fluid (CSF) of glioma patients that carry point substitutions in the IDH gene. Experimental Design: We developed a mass spectrometry (MS)-based platform to detect and quantify the D- and L-forms of 2HG in the CSF of glioma patients. Three independent cohorts of patients were analyzed, comprising a total of 176 samples derived from 84 patients. The levels of D- and L-2HG were used to stratify patients into IDH wild-type or IDH-mutated groups using an empirically obtained threshold of 0.69 μmol/L. Results: Using this platform, a greater than 17-fold mean increase in D-2HG was observed in the CSF of patients with IDH mutant versus wild-type gliomas. The means for the D-2HG levels in CSF were 0.427 μmol/L in wild-type and 7.439 μmol/L in mutant groups. The C statistic for the receiver operator curve was 0.938, with 84% sensitivity, 90% specificity, and 89% accuracy to detect D-2HG. The levels of D- and L-2HG in CSF from wild-type patients varied by location of CSF draw (cisternal>ventricular>lumbar). Conclusions: Our findings demonstrate that the CSF of patients harboring IDH mutant gliomas contain increased levels of D-2HG, which can be reliably detected with a MS-based platform.

Original language	English (US)
Pages (from-to)	6256-6265
Number of pages	10
Journal	Clinical Cancer Research
Volume	22
Issue number	24
DOIs	https://doi.org/10.1158/1078-0432.CCR-15-2965
State	Published - Dec 15 2016

Bibliographical note

Funding Information:
J.J. Olson reports receiving commercial research grants from Genentech and Millennium and other commercial research support from Merck. R.L. Jensen is a consultant/advisory board member for Medtronic, Pharmacokinesis, and Varian. No potential conflicts of interest were disclosed by the other authors. We thank Narra Sarojini Devi, Milton Merchant, Lawrence Recht and Zhaobin Zhang for help with patient sample banking. This work was supported in part by grants from the NIH (CA086335, CA116804, NS096236 to E.G. Van Meir, CA169937 to H. Mao, CA138292 to Walter Curran, Winship Cancer Institute), NINDS training grant 2T32NS007480-11 (to J. Kalinina and Allan I. Levey), the Brain Tumor Funders Collaborative (to E.G. Van Meir), and the Georgia Cancer Coalition (to J. Kalinina and E.G. Van Meir). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Publisher Copyright:
©2016 AACR.

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Kalinina, J., Ahn, J., Devi, N. S., Wang, L., Li, Y., Olson, J. J., Glantz, M., Smith, T., Kim, E. L., Giese, A., Jensen, R. L., Chen, C. C., Carter, B. S., Mao, H., He, M., & Van Meir, E. G. (2016). Selective detection of the D-enantiomer of 2-hydroxyglutarate in the CSF of glioma patients with mutated isocitrate dehydrogenase. Clinical Cancer Research, 22(24), 6256-6265. https://doi.org/10.1158/1078-0432.CCR-15-2965

Kalinina, J, Ahn, J, Devi, NS, Wang, L, Li, Y, Olson, JJ, Glantz, M, Smith, T, Kim, EL, Giese, A, Jensen, RL, Chen, CC, Carter, BS, Mao, H, He, M & Van Meir, EG 2016, 'Selective detection of the D-enantiomer of 2-hydroxyglutarate in the CSF of glioma patients with mutated isocitrate dehydrogenase', Clinical Cancer Research, vol. 22, no. 24, pp. 6256-6265. https://doi.org/10.1158/1078-0432.CCR-15-2965

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title = "Selective detection of the D-enantiomer of 2-hydroxyglutarate in the CSF of glioma patients with mutated isocitrate dehydrogenase",

abstract = "Purpose: Elevation in D-2-Hydroxyglutarate (D-2HG) has recently emerged as a mandatory byproduct of mutated Isocitrate Dehydrogenase (IDH) genes 1 and 2 in glioma patients. The goal of the present study was to demonstrate the feasibility of detection of elevated levels of D-2HG in the cerebrospinal fluid (CSF) of glioma patients that carry point substitutions in the IDH gene. Experimental Design: We developed a mass spectrometry (MS)-based platform to detect and quantify the D- and L-forms of 2HG in the CSF of glioma patients. Three independent cohorts of patients were analyzed, comprising a total of 176 samples derived from 84 patients. The levels of D- and L-2HG were used to stratify patients into IDH wild-type or IDH-mutated groups using an empirically obtained threshold of 0.69 μmol/L. Results: Using this platform, a greater than 17-fold mean increase in D-2HG was observed in the CSF of patients with IDH mutant versus wild-type gliomas. The means for the D-2HG levels in CSF were 0.427 μmol/L in wild-type and 7.439 μmol/L in mutant groups. The C statistic for the receiver operator curve was 0.938, with 84% sensitivity, 90% specificity, and 89% accuracy to detect D-2HG. The levels of D- and L-2HG in CSF from wild-type patients varied by location of CSF draw (cisternal>ventricular>lumbar). Conclusions: Our findings demonstrate that the CSF of patients harboring IDH mutant gliomas contain increased levels of D-2HG, which can be reliably detected with a MS-based platform.",

author = "Juliya Kalinina and Jun Ahn and Devi, {Narra S.} and Liya Wang and Yuancheng Li and Olson, {Jeffrey J.} and Michael Glantz and Thomas Smith and Kim, {Ella L.} and Alf Giese and Jensen, {Randy L.} and Chen, {Clark C.} and Carter, {Bob S.} and Hui Mao and Miao He and {Van Meir}, {Erwin G.}",

note = "Funding Information: J.J. Olson reports receiving commercial research grants from Genentech and Millennium and other commercial research support from Merck. R.L. Jensen is a consultant/advisory board member for Medtronic, Pharmacokinesis, and Varian. No potential conflicts of interest were disclosed by the other authors. We thank Narra Sarojini Devi, Milton Merchant, Lawrence Recht and Zhaobin Zhang for help with patient sample banking. This work was supported in part by grants from the NIH (CA086335, CA116804, NS096236 to E.G. Van Meir, CA169937 to H. Mao, CA138292 to Walter Curran, Winship Cancer Institute), NINDS training grant 2T32NS007480-11 (to J. Kalinina and Allan I. Levey), the Brain Tumor Funders Collaborative (to E.G. Van Meir), and the Georgia Cancer Coalition (to J. Kalinina and E.G. Van Meir). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: {\textcopyright}2016 AACR.",

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AU - Kalinina, Juliya

AU - Ahn, Jun

AU - Devi, Narra S.

AU - Wang, Liya

AU - Li, Yuancheng

AU - Olson, Jeffrey J.

AU - Glantz, Michael

AU - Smith, Thomas

AU - Kim, Ella L.

AU - Giese, Alf

AU - Jensen, Randy L.

AU - Chen, Clark C.

AU - Carter, Bob S.

AU - Mao, Hui

AU - He, Miao

AU - Van Meir, Erwin G.

N1 - Funding Information: J.J. Olson reports receiving commercial research grants from Genentech and Millennium and other commercial research support from Merck. R.L. Jensen is a consultant/advisory board member for Medtronic, Pharmacokinesis, and Varian. No potential conflicts of interest were disclosed by the other authors. We thank Narra Sarojini Devi, Milton Merchant, Lawrence Recht and Zhaobin Zhang for help with patient sample banking. This work was supported in part by grants from the NIH (CA086335, CA116804, NS096236 to E.G. Van Meir, CA169937 to H. Mao, CA138292 to Walter Curran, Winship Cancer Institute), NINDS training grant 2T32NS007480-11 (to J. Kalinina and Allan I. Levey), the Brain Tumor Funders Collaborative (to E.G. Van Meir), and the Georgia Cancer Coalition (to J. Kalinina and E.G. Van Meir). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: ©2016 AACR.

PY - 2016/12/15

Y1 - 2016/12/15

N2 - Purpose: Elevation in D-2-Hydroxyglutarate (D-2HG) has recently emerged as a mandatory byproduct of mutated Isocitrate Dehydrogenase (IDH) genes 1 and 2 in glioma patients. The goal of the present study was to demonstrate the feasibility of detection of elevated levels of D-2HG in the cerebrospinal fluid (CSF) of glioma patients that carry point substitutions in the IDH gene. Experimental Design: We developed a mass spectrometry (MS)-based platform to detect and quantify the D- and L-forms of 2HG in the CSF of glioma patients. Three independent cohorts of patients were analyzed, comprising a total of 176 samples derived from 84 patients. The levels of D- and L-2HG were used to stratify patients into IDH wild-type or IDH-mutated groups using an empirically obtained threshold of 0.69 μmol/L. Results: Using this platform, a greater than 17-fold mean increase in D-2HG was observed in the CSF of patients with IDH mutant versus wild-type gliomas. The means for the D-2HG levels in CSF were 0.427 μmol/L in wild-type and 7.439 μmol/L in mutant groups. The C statistic for the receiver operator curve was 0.938, with 84% sensitivity, 90% specificity, and 89% accuracy to detect D-2HG. The levels of D- and L-2HG in CSF from wild-type patients varied by location of CSF draw (cisternal>ventricular>lumbar). Conclusions: Our findings demonstrate that the CSF of patients harboring IDH mutant gliomas contain increased levels of D-2HG, which can be reliably detected with a MS-based platform.

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Selective detection of the D-enantiomer of 2-hydroxyglutarate in the CSF of glioma patients with mutated isocitrate dehydrogenase

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