title: Selective Detection of the D-enantiomer of 2-Hydroxyglutarate in the CSF of Glioma Patients with Mutated Isocitrate Dehydrogenase.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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. Clin Cancer Res; 22(24); 6256-65. ©2016 AACR.
authors.affiliation: Department of Neurosurgery, Emory University, Atlanta, Georgia.
authors.forename: Juliya
authors.initials: J
authors.lastname: Kalinina
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia.
authors.forename: Jun
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Department of Neurosurgery, Emory University, Atlanta, Georgia.
authors.forename: Narra S
authors.initials: NS
authors.lastname: Devi
authors.affiliation: Department of Radiology, School of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Radiology, School of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Yuancheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Emory University, Atlanta, Georgia.|Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.affiliation: Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Glantz
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: Smith
authors.affiliation: University of Medical Center of Mainz, Mainz, Germany.
authors.forename: Ella L
authors.initials: EL
authors.lastname: Kim
authors.affiliation: University of Medical Center of Mainz, Mainz, Germany.
authors.forename: Alf
authors.initials: A
authors.lastname: Giese
authors.affiliation: Hunstman Cancer Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Jensen
authors.affiliation: University of California, San Diego, La Jolla, California.
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
authors.affiliation: University of California, San Diego, La Jolla, California.
authors.forename: Bob S
authors.initials: BS
authors.lastname: Carter
authors.affiliation: Department of Radiology, School of Medicine, Emory University, Atlanta, Georgia.|Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, Georgia.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Neurosurgery, Emory University, Atlanta, Georgia. evanmei@emory.edu.|Winship Cancer Institute, Emory University, Atlanta, Georgia.|Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia.
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid / Q000235:genetics*; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000134:cerebrospinal fluid / Q000235:genetics*; D005977:Glutarates / Q000134:cerebrospinal fluid*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D055815:Young Adult
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase