Abstract
Mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or its mitochondrial homolog IDH2 can lead to R(−)-2-hydroxyglutarate (2HG) production. To date, mutations in three active site arginine residues, IDH1 R132, IDH2 R172 and IDH2 R140, have been shown to result in the neomorphic production of 2HG. Here we report on three additional 2HG-producing IDH1 mutations: IDH1 R100, which is affected in adult glioma, IDH1 G97, which is mutated in colon cancer cell lines and pediatric glioblastoma, and IDH1 Y139. All these new mutants stereospecifically produced 2HG's (R) enantiomer. In contrast, we find that the IDH1 SNPs V71I and V178I, as well as a number of other single-sample reports of IDH non-synonymous mutation, did not elevate cellular 2HG levels in cells and retained the wild-type ability for isocitrate-dependent NADPH production. Finally, we report the existence of additional rare, but recurring mutations found in lymphoma and thyroid cancer, which while failing to elevate 2HG nonetheless displayed loss of function, indicating a possible tumorigenic mechanism for a non-2HG-producing subset of IDH mutations in some malignancies. These data broaden our understanding of how IDH mutations may contribute to cancer through either neomorphic R(−)-2HG production or reduced wild-type enzymatic activity, and highlight the potential value of metabolite screening in identifying IDH-mutated tumors associated with elevated oncometabolite levels.
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References
Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F et al. (2011). IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224: 334–343.
Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP et al. (2009). IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 30: 7–11.
Ceccarelli C, Grodsky NB, Ariyaratne N, Colman RF, Bahnson BJ . (2002). Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism. J Biol Chem 277: 43454–43462.
Cooper DN, Youssoufian H . (1988). The CpG dinucleotide and human genetic disease. Hum Genet 78: 151–155.
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462: 739–744.
DeLano WL . (2006). The PyMOL Molecular Graphics System. DeLano Scientific.
Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. (2010). Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18: 553–567.
Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D et al. (2011). COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 39: D945–D950.
Hemerly JP, Bastos AU, Cerutti JM . (2010). Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur J Endocrinol 163: 747–755.
Ho PA, Alonzo TA, Kopecky KJ, Miller KL, Kuhn J, Zeng R et al. (2010). Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study. Leukemia 24: 909–913.
Jin G, Reitman ZJ, Spasojevic I, Batinic-Haberle I, Yang J, Schmidt-Kittler O et al. (2011). 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations. PLoS One 6: e16812.
Kamerling JP, Duran M, Gerwig GJ, Ketting D, Bruinvis L, Vliegenthart JF et al. (1981). Determination of the absolute configuration of some biologically important urinary 2-hydroxydicarboxylic acids by capillary gas—liquid chromatography. J Chromatogr 222: 276–283.
Kranendijk M, Struys EA, van Schaftingen E, Gibson KM, Kanhai WA, van der Knaap MS et al. (2010). IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330: 336.
Lemons JM, Feng XJ, Bennett BD, Legesse-Miller A, Johnson EL, Raitman I et al. (2010). Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol 8: e1000514.
Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D et al. (2010). IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 28: 2348–2355.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. (2009). Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361: 1058–1066.
Murugan AK, Bojdani E, Xing M . (2010). Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun 393: 555–559.
Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al. (2010). Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17: 510–522.
Parsons DW, Jones S, Zhang X, Lin JC, Leary LJ, Angenendt P et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science 321: 1807–1812.
Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J et al. (2010). Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28: 3061–3068.
Pusch S, Sahm F, Meyer J, Mittelbronn M, Hartmann C, von Deimling A . (2011). Glioma IDH1 mutation patterns off the beaten track. Neuropathol Appl Neurobiol 37: 428–430.
Rakheja D, Mitui M, Boriack RL, DeBerardinis RJ . (2011). Isocitrate dehydrogenase 1/2 mutational analyses and 2-hydroxyglutarate measurements in Wilms tumors. Pediatr Blood Cancer 56: 379–383.
Shibata T, Kokubu A, Miyamoto M, Sasajima Y, Yamazaki N . (2011). Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation. Am J Pathol 178: 1395–1402.
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. (2010). The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225–234.
Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E et al. (2004). Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem 279: 33946–33957.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al. (2009). IDH1 and IDH2 mutations in gliomas. N Engl J Med 360: 765–773.
Zou Y, Zeng Y, Zhang DF, Zou SH, Cheng YF, Yao YG . (2010). IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders. Biochem Biophys Res Commun 402: 378–383.
Acknowledgements
This work was supported in part by grants from the NCI and NIH. RL Levine is a HHMI Early Career Award Recipient and Geoffrey Beene Junior Faculty Chair at MSKCC. DM Weinstock is supported by a Stand Up To Cancer Innovative Research Grant and American Cancer Society Research Scholar Grant.
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Dr Thompson's work has been funded by the NCI and NIH. He is a co-founder of Agios Pharmaceuticals, is the chair of its scientific advisory board and has financial interest in the company. The remaining authors declare no conflict of interest.
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Ward, P., Cross, J., Lu, C. et al. Identification of additional IDH mutations associated with oncometabolite R(−)-2-hydroxyglutarate production. Oncogene 31, 2491–2498 (2012). https://doi.org/10.1038/onc.2011.416
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DOI: https://doi.org/10.1038/onc.2011.416
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