title: Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma.
abstract: BACKGROUND
  Recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated.
  
  
  METHODS
  In this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDH-wild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort.
  
  
  RESULTS
  We found that 2-HG was elevated in the urine of patients with IDH-mutant versus IDH-wild-type glioma, although no significant differences in 2-HG levels were observed in the serum or the small set of CSF samples obtained. Among patients with IDH-mutant glioma, 2-HG levels did not differ based on the histopathologic grade, genetic subtype (TP53 mutant or 1p/19q codeleted), presence of a canonical (IDH1 R132H) or noncanonical (any other IDH variant) mutation, or treatment type.
  
  
  CONCLUSIONS
  Our finding suggests that urinary 2-HG is increased among patients with IDH-mutant gliomas, and may represent a future surrogate, noninvasive biomarker to aid in diagnosis, prognosis, and management.
  
  
  CONCLUSIONS
  Patients with glioma who harbor mutations in isocitrate dehydrogenase genes showed selective elevation of the oncometabolite 2-hydroxyglutarate in the urine. Similar elevations were not identified in the serum or cerebrospinal fluid. 2-Hydroxyglutarate may serve as a useful, noninvasive biomarker to stratify patients newly diagnosed with glioma with regard to prognosis and management.
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA afathi@partners.org.
authors.forename: Amir T
authors.initials: AT
authors.lastname: Fathi
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Brian V
authors.initials: BV
authors.lastname: Nahed
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Seth A
authors.initials: SA
authors.lastname: Wander
authors.affiliation: Translational Research Laboratory, Cancer Center, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Translational Research Laboratory, Cancer Center, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.affiliation: Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ranliang
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Thabet
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Perry
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christelle P
authors.initials: CP
authors.lastname: Joseph
authors.affiliation: Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.affiliation: Division of Neuro-Oncology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA Division of Hematology/Oncology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000652:urine*; D005260:Female; D005838:Genotype; D005910:Glioma / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000652:urine*; D005977:Glutarates / Q000097:blood / Q000652:urine*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: D014408:Biomarkers, Tumor; D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: 2-Hydroxyglutarate; Glioma; Isocitrate dehydrogenase; Novel biomarkers; Targeted therapies
references.citation: N Engl J Med. 2009 Feb 19;360(8):765-73
references.pmid: 19228619
references.citation: Hum Mutat. 2009 Jan;30(1):7-11
references.pmid: 19117336
references.citation: Science. 2009 Apr 10;324(5924):261-5
references.pmid: 19359588
references.citation: J Clin Oncol. 2009 Sep 1;27(25):4150-4
references.pmid: 19636000
references.citation: Acta Neuropathol. 2009 Oct;118(4):469-74
references.pmid: 19554337
references.citation: Nature. 2009 Dec 10;462(7274):739-44
references.pmid: 19935646
references.citation: J Exp Med. 2010 Feb 15;207(2):339-44
references.pmid: 20142433
references.citation: Cancer Cell. 2010 Mar 16;17(3):225-34
references.pmid: 20171147
references.citation: Brain Pathol. 2010 Jan;20(1):245-54
references.pmid: 19903171
references.citation: EMBO Mol Med. 2010 May;2(5):146-58
references.pmid: 20432502
references.citation: Acta Neuropathol. 2010 Dec;120(6):707-18
references.pmid: 21088844
references.citation: Cancer Cell. 2010 Dec 14;18(6):553-67
references.pmid: 21130701
references.citation: Cancer Cell. 2011 Jan 18;19(1):17-30
references.pmid: 21251613
references.citation: EMBO Rep. 2011 May;12(5):463-9
references.pmid: 21460794
references.citation: Science. 2011 Sep 9;333(6048):1453-5
references.pmid: 21817013
references.citation: J Clin Oncol. 2011 Dec 1;29(34):4482-90
references.pmid: 22025148
references.citation: Sci Transl Med. 2012 Jan 11;4(116):116ra4
references.pmid: 22238332
references.citation: Neuro Oncol. 2012 Feb;14(2):184-91
references.pmid: 22166263
references.citation: Nature. 2012 Mar 22;483(7390):479-83
references.pmid: 22343889
references.citation: Nature. 2012 Mar 22;483(7390):484-8
references.pmid: 22343896
references.citation: Nature. 2012 Mar 22;483(7390):474-8
references.pmid: 22343901
references.citation: Int J Cancer. 2012 Aug 1;131(3):766-8
references.pmid: 21913188
references.citation: Oncotarget. 2012 Jul;3(7):709-22
references.pmid: 22869205
references.citation: Nature. 2012 Aug 30;488(7413):656-9
references.pmid: 22763442
references.citation: Blood. 2012 Nov 29;120(23):4649-52
references.pmid: 23074281
references.citation: Science. 2013 Mar 29;339(6127):1621-5
references.pmid: 23393090
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6021-6
references.pmid: 23530248
references.citation: J Neurooncol. 2013 May;113(1):65-74
references.pmid: 23456655
references.citation: J Clin Invest. 2013 Sep;123(9):3659-63
references.pmid: 23999439
references.citation: Neuro Oncol. 2014 Jan;16(1):81-91
references.pmid: 24305719
references.citation: Science. 2014 Jan 10;343(6167):189-93
references.pmid: 24336570
references.citation: Clin Cancer Res. 2014 Apr 1;20(7):1884-90
references.pmid: 24478380
references.citation: Oncotarget. 2014 Mar 30;5(6):1515-25
references.pmid: 24722048
references.citation: Oncologist. 2014 Jun;19(6):602-7
references.pmid: 24760710
references.citation: Nature. 2014 Sep 4;513(7516):110-4
references.pmid: 25043045
references.citation: Oncologist. 2015 May;20(5):562-7
references.pmid: 25862748
references.citation: J Mol Diagn. 2006 May;8(2):268-76
references.pmid: 16645215
references.citation: Science. 2008 Sep 26;321(5897):1807-12
references.pmid: 18772396
references.citation: Am J Pathol. 2009 Apr;174(4):1149-53
references.pmid: 19246647