Journal
CLINICAL CANCER RESEARCH
Volume 22, Issue 24, Pages 6256-6265Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-15-2965
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Funding
- NIH [CA086335, CA116804, NS096236, CA169937, CA138292]
- NINDS [2T32NS007480-11]
- Brain Tumor Funders Collaborative
- Georgia Cancer Coalition
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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 mu mol/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 mu mol/L in wild-type and 7.439 mmol/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. (C)2016 AACR.
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