Tumor Biology

, Volume 32, Issue 2, pp 325–333 | Cite as

Papillary thyroid carcinoma shows elevated levels of 2-hydroxyglutarate

  • Dinesh Rakheja
  • Richard L. Boriack
  • Midori Mitui
  • Shama Khokhar
  • Shelby A. Holt
  • Payal Kapur
Research Article


Elevated levels of d-2-hydroxyglutarate (d-2-HG) occur in gliomas and myeloid leukemias associated with mutations of IDH1 and IDH2. l-2-Hydroxyglutaric aciduria, an inherited metabolic disorder, predisposes to brain tumors. Therefore, we asked whether sporadic cancers, without IDH1 or IDH2 hot-spot mutations, show elevated 2-hydroxyglutarate levels. We retrieved 15 pairs of frozen papillary thyroid carcinoma (PTC) and adjacent non-neoplastic thyroid, and 14 pairs of hyperplastic nodule (HN) and adjacent non-hyperplastic thyroid. In all lesions, exon 4 sequencing confirmed the absence of known mutations of IDH1 and IDH2. We measured 2-hydroxyglutarate by liquid chromatography-tandem mass spectrometry. Compared to normal thyroid, PTCs had significantly higher d-2-HG and l-2-hydroxyglutarate (l-2-HG) levels, and compared to HNs, PTCs had significantly higher d-2-HG levels. d-2-HG/l-2-HG levels were not significantly different between HNs and normal thyroid. Further studies should clarify if elevated 2-hydroxyglutarate in PTC may be useful as cancer biomarker and evaluate the role of 2-hydroxyglutarate in cancer biology.


2-Hydroxyglutarate Isocitrate dehydrogenase Papillary thyroid carcinoma Thyroid cancer 


  1. 1.
    Struys EA. d-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect. J Inherit Metab Dis. 2006;29:21–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Van Schaftingen E, Rzem R, Veiga-da-Cunha M. l-2-Hydroxyglutaric aciduria, a disorder of metabolite repair. J Inherit Metab Dis. 2009;32:135–42.CrossRefPubMedGoogle Scholar
  3. 3.
    Moroni I, Bugiani M, D’Incerti L, Maccagnano C, Rimoldi M, Bissola L, et al. l-2-Hydroxyglutaric aciduria and brain malignant tumors: a predisposing condition? Neurology. 2004;62:1882–4.PubMedGoogle Scholar
  4. 4.
    Wilcken B, Pitt J, Heath D, Walsh P, Wilson G, Buchanan N. l-2-Hydroxyglutaric aciduria: three australian cases. J Inherit Metab Dis. 1993;16:501–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Barbot C, Fineza I, Diogo L, Maia M, Melo J, Guimaraes A, et al. l-2-Hydroxyglutaric aciduria: clinical, biochemical and magnetic resonance imaging in six portuguese pediatric patients. Brain Dev. 1997;19:268–73.CrossRefPubMedGoogle Scholar
  6. 6.
    Ozisik PA, Akalan N, Palaoglu S, Topcu M. Medulloblastoma in a child with the metabolic disease l-2-hydroxyglutaric aciduria. Pediatr Neurosurg. 2002;37:22–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Haliloglu G, Jobard F, Oguz KK, Anlar B, Akalan N, Coskun T, et al. l-2-Hydroxyglutaric aciduria and brain tumors in children with mutations in the l2hgdh gene: neuroimaging findings. Neuropediatrics. 2008;39:119–22.CrossRefPubMedGoogle Scholar
  8. 8.
    Aghili M, Zahedi F, Rafiee E. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J Neurooncol. 2009;91:233–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Larnaout A, Amouri R, Neji S, Zouari M, Kaabachi N, Hentati F. Osteoma of the calvaria in l-2-hydroxyglutaric aciduria. J Inherit Metab Dis. 2007;30:980.CrossRefPubMedGoogle Scholar
  10. 10.
    Rogers RE, Deberardinis RJ, Klesse LJ, Boriack RL, Margraf L, Rakheja D. Wilms tumor in a child with l-2-hydroxyglutaric aciduria. Pediatr Dev Pathol. 2010.Google Scholar
  11. 11.
    Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34.CrossRefPubMedGoogle Scholar
  12. 12.
    Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207:339–44.CrossRefPubMedGoogle Scholar
  13. 13.
    Frezza C, Tennant DA, Gottlieb E. IDH1 mutations in gliomas: when an enzyme loses its grip. Cancer Cell. 2010;17:7–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:739–44.CrossRefPubMedGoogle Scholar
  15. 15.
    Hemerly JP, Bastos AU, Cerutti JM. Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur J Endocrinol. 2010;163:747–55.CrossRefPubMedGoogle Scholar
  16. 16.
    Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, et al. IDH1 mutations at residue p.R132 (IDH1(r132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat. 2009;30:7–11.CrossRefPubMedGoogle Scholar
  17. 17.
    Murugan AK, Bojdani E, Xing M. Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun. 2010.Google Scholar
  18. 18.
    Gibson KM, ten Brink HJ, Schor DS, Kok RM, Bootsma AH, Hoffmann GF, et al. Stable-isotope dilution analysis of d- and l-2-hydroxyglutaric acid: application to the detection and prenatal diagnosis of d- and l-2-hydroxyglutaric acidemias. Pediatr Res. 1993;34:277–80.CrossRefPubMedGoogle Scholar
  19. 19.
    Lu W, Kimball E, Rabinowitz JD. A high-performance liquid chromatography-tandem mass spectrometry method for quantitation of nitrogen-containing intracellular metabolites. J Am Soc Mass Spectrom. 2006;17:37–50.CrossRefPubMedGoogle Scholar
  20. 20.
    Struys EA, Jansen EE, Verhoeven NM, Jakobs C. Measurement of urinary d- and l-2-hydroxyglutarate enantiomers by stable-isotope-dilution liquid chromatography-tandem mass spectrometry after derivatization with diacetyl-l-tartaric anhydride. Clin Chem. 2004;50:1391–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–73.CrossRefPubMedGoogle Scholar
  22. 22.
    Green A, Beer P. Somatic mutations of IDH1 and IDH2 In the leukemic transformation of myeloproliferative neoplasms. N Engl J Med. 2010;362:369–70.CrossRefPubMedGoogle Scholar
  23. 23.
    Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–66.CrossRefPubMedGoogle Scholar
  24. 24.
    Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.CrossRefPubMedGoogle Scholar
  25. 25.
    Struys EA, Verhoeven NM, Jansen EE, Ten Brink HJ, Gupta M, Burlingame TG, et al. Metabolism of gamma-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase. Metabolism. 2006;55:353–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Struys EA, Verhoeven NM, Ten Brink HJ, Wickenhagen WV, Gibson KM, Jakobs C. Kinetic characterization of human HOT: relevance to d-2-hydroxyglutaric and gamma-hydroxybutyric acidurias. J Inherit Metab Dis. 2005;28:921–30.CrossRefPubMedGoogle Scholar
  27. 27.
    Steenweg ME, Jakobs C, Errami A, van Dooren SJ, Adeva Bartolome MT, Aerssens P, et al. An overview of l-2-hydroxyglutarate dehydrogenase gene (l2hgdh) variants: a genotype-phenotype study. Hum Mutat. 2010;31:380–90.CrossRefPubMedGoogle Scholar
  28. 28.
    Topcu M, Jobard F, Halliez S, Coskun T, Yalcinkayal C, Gerceker FO, et al. l-2-Hydroxyglutaric aciduria: identification of a mutant gene c14orf160, localized on chromosome 14q22.1. Hum Mol Genet. 2004;13:2803–11.CrossRefPubMedGoogle Scholar
  29. 29.
    Rzem R, Veiga-da-Cunha M, Noel G, Goffette S, Nassogne MC, Tabarki B, et al. A gene encoding a putative fad-dependent l-2-hydroxyglutarate dehydrogenase is mutated in l-2-hydroxyglutaric aciduria. Proc Natl Acad Sci USA. 2004;101:16849–54.CrossRefPubMedGoogle Scholar
  30. 30.
    Kranendijk M, Struys EA, Gibson KM, Wickenhagen WV, Abdenur JE, Buechner J, et al. Evidence for genetic heterogeneity in d-2-hydroxyglutaric aciduria. Hum Mutat. 2009;31:279–83.CrossRefGoogle Scholar
  31. 31.
    Struys EA, Korman SH, Salomons GS, Darmin PS, Achouri Y, van Schaftingen E, et al. Mutations in phenotypically mild d-2-hydroxyglutaric aciduria. Ann Neurol. 2005;58:626–30.CrossRefPubMedGoogle Scholar
  32. 32.
    Struys EA, Salomons GS, Achouri Y, Van Schaftingen E, Grosso S, Craigen WJ, et al. Mutations in the d-2-hydroxyglutarate dehydrogenase gene cause d-2-hydroxyglutaric aciduria. Am J Hum Genet. 2005;76:358–60.CrossRefPubMedGoogle Scholar
  33. 33.
    Muntau AC, Roschinger W, Merkenschlager A, van der Knaap MS, Jakobs C, Duran M, et al. Combined d-2- and l-2-hydroxyglutaric aciduria with neonatal onset encephalopathy: a third biochemical variant of 2-hydroxyglutaric aciduria? Neuropediatrics. 2000;31:137–40.CrossRefPubMedGoogle Scholar
  34. 34.
    Read MH, Bonamy C, Laloum D, Belloy F, Constans JM, Guillois B, et al. Clinical, biochemical, magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1 H MRS) findings in a fourth case of combined d- and l-2 hydroxyglutaric aciduria. J Inherit Metab Dis. 2005;28:1149–50.CrossRefPubMedGoogle Scholar
  35. 35.
    Angle B, Burton BK. Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II. Mol Genet Metab. 2008;93:36–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Yee WC. Two eminently treatable genetic metabolic myopathies. Neurol India. 2008;56:333–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Yazici N, Sarialioglu F, Alkan O, Kayaselcuk F, Erol I. l-2-Hydroxyglutaric aciduria and brain tumors: a case report and review of the literature. J Pediatr Hematol Oncol. 2009;31:865–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Rakheja D. l-2-Hydroxyglutaric aciduria and multiple acyl-coenzyme a dehydrogenase deficiency are distinct metabolic disorders. J Pediatr Hematol Oncol. 2010;32:169–70.CrossRefPubMedGoogle Scholar
  39. 39.
    Reitman ZJ, Parsons DW, Yan H. IDH1 and IDH2: not your typical oncogenes. Cancer Cell. 2010;17:215–6.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2010

Authors and Affiliations

  • Dinesh Rakheja
    • 1
    • 2
  • Richard L. Boriack
    • 1
  • Midori Mitui
    • 1
  • Shama Khokhar
    • 1
  • Shelby A. Holt
    • 3
  • Payal Kapur
    • 2
  1. 1.Department of Pathology, Children’s Medical CenterDallasUSA
  2. 2.Department of PathologyUniversity of Texas (UT) Southwestern Medical CenterDallasUSA
  3. 3.Department of SurgeryUniversity of Texas (UT) Southwestern Medical CenterDallasUSA

Personalised recommendations