Abstract
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.
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Struys EA. d-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect. J Inherit Metab Dis. 2006;29:21–9.
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.
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.
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.
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.
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.
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.
Aghili M, Zahedi F, Rafiee E. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J Neurooncol. 2009;91:233–6.
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.
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.
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.
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.
Frezza C, Tennant DA, Gottlieb E. IDH1 mutations in gliomas: when an enzyme loses its grip. Cancer Cell. 2010;17:7–9.
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.
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.
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.
Murugan AK, Bojdani E, Xing M. Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun. 2010.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Yee WC. Two eminently treatable genetic metabolic myopathies. Neurol India. 2008;56:333–8.
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.
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.
Reitman ZJ, Parsons DW, Yan H. IDH1 and IDH2: not your typical oncogenes. Cancer Cell. 2010;17:215–6.
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Rakheja, D., Boriack, R.L., Mitui, M. et al. Papillary thyroid carcinoma shows elevated levels of 2-hydroxyglutarate. Tumor Biol. 32, 325–333 (2011). https://doi.org/10.1007/s13277-010-0125-6
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DOI: https://doi.org/10.1007/s13277-010-0125-6