Oncometabolites-driven tumorigenesis: From genetics to targeted therapy

International Journal of Cancer

Volumn 135, Issue 10, 2014, Pages 2237-2248

  Morin, Aurélie ^a,b   Letouzé, Eric ^c   Gimenez Roqueplo, Anne Paule ^a,b   Favier, Judith ^a,b  

^a HÔPITAL EUROPÉEN GEORGES POMPIDOU   (France)

^b UNIVERSITÉ PARIS DESCARTES   (France)

^c Ligue Nationale Contre le Cancer   (France)

Author keywords

Epigenetics; FH; Glioblastoma; Hypoxia; IDH; Metabolism; Oncometabolite; Paraganglioma; Pheochromocytoma; SDH

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; ALKYLATING AGENT; AZACITIDINE; BEVACIZUMAB; DIOXYGENASE; FUMARATE HYDRATASE; ISOCITRATE DEHYDROGENASE; ISOCITRATE DEHYDROGENASE 1; ISOCITRATE DEHYDROGENASE 2; ONCOMETABOLITE; OXYGENASE; SGI 110; SORAFENIB; SUCCINATE DEHYDROGENASE; SUNITINIB; TEMOZOLOMIDE; TUMOR MARKER; UNCLASSIFIED DRUG; ZEBULARINE;

ACUTE GRANULOCYTIC LEUKEMIA; ANTIANGIOGENIC THERAPY; APOPTOSIS; CANCER CHEMOTHERAPY; CANCER GENETICS; CANCER SUSCEPTIBILITY; CARCINOGENESIS; CELL METABOLISM; DNA METHYLATION; DRUG CYTOTOXICITY; DRUG MEGADOSE; DRUG TARGETING; ENZYME REACTIVATION; EPIGENETICS; GASTROINTESTINAL STROMAL TUMOR; GLIOBLASTOMA; HISTONE MODIFICATION; HUMAN; HYPOXIA; KIDNEY CANCER; KIDNEY CARCINOMA; LEIOMYOMA; LOW DRUG DOSE; METASTASIS; MYELODYSPLASTIC SYNDROME; NONHUMAN; PARAGANGLIOMA; PHEOCHROMOCYTOMA; REVIEW; CELL TRANSFORMATION; FH; GENETICS; IDH; METABOLISM; METABOLOME; NEOPLASM; ONCOMETABOLITE; PATHOLOGY;

EPIGENETICS; FH; GLIOBLASTOMA; HYPOXIA; IDH; METABOLISM; ONCOMETABOLITE; PARAGANGLIOMA; PHEOCHROMOCYTOMA; SDH;

CELL TRANSFORMATION, NEOPLASTIC; HUMANS; METABOLOME; NEOPLASMS;

EID: 84909951484     PISSN: 00207136     EISSN: 10970215     Source Type: Journal    
DOI: 10.1002/ijc.29080     Document Type: Review

References (149)

1. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 2012;21:297-308.
2. Warburg O. Ueber den stoffwechsel der tumoren. London: Constable, 1930.
3. Galluzzi L, Kepp O, Vander Heiden MG, et al. Metabolic targets for cancer therapy. Nat Rev Drug Discov 2013;12:829-46.
4. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324:1029-33.
5. Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000;287:848-51.
6. Burnichon N, Briere JJ, Libe R, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 2010;19:3011-20.
7. Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001;69:49-54.
8. Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000;26:268-70.
9. Bayley JP, Kunst HP, Cascon A, et al. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 2010;11:366-72.
10. Janeway KA, Kim SY, Lodish M, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA 2011;108:314-18.
11. Italiano A, Chen CL, Sung YS, et al. SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors. BMC Cancer 2012;12:408.
12. Ricketts C, Woodward ER, Killick P, et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 2008;100:1260-2.
13. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30:406-10.
14. Castro-Vega LJ, Buffet A, de Cubas AA, et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 2014;23:2440-6.
15. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008;321:1807-12.
16. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009;361:1058-66.
17. Amary MF, Bacsi K, Maggiani F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 2011;224:334-43.
18. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 2012;17:72-9.
19. Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009;462:739-44.
20. Pollard PJ, Briere JJ, Alam NA, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005;14:2231-9.
21. Rodriguez-Cuevas S, Lopez-Garza J, Labastida-Almendaro S. Carotid body tumors in inhabitants of altitudes higher than 2000 meters above sea level. Head Neck 1998;20:374-8.
22. Gimenez-Roqueplo AP, Favier J, Rustin P, et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 2001;69:1186-97.
23. Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab 2002;87:4771-4.
24. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001;107:43-54.
25. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292:468-72.
26. Lando D, Peet DJ, Gorman JJ, et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 2002;16:1466-71.
27. Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005;7:77-85.
28. Briere JJ, Favier J, Benit P, et al. Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions. Hum Mol Genet 2005;14:3263-9.
29. Dahia PL, Ross KN, Wright ME, et al. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 2005;1:72-80.
30. Burnichon N, Vescovo L, Amar L, et al. Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet 2011;20:3974-85.
31. Lopez-Jimenez E, Gomez-Lopez G, Leandro-Garcia LJ, et al. Research resource: transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol Endocrinol 2010;24:2382-91.
32. Loriot C, Burnichon N, Gadessaud N, et al. Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations. J Clin Endocrinol Metab 2012;97:E954-E962.
33. Favier J, Briere JJ, Burnichon N, et al. The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One 2009;4:e7094.
34. Guzy RD, Sharma B, Bell E, et al. Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol 2008;28:718-31.
35. Isaacs JS, Jung YJ, Mole DR, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005;8:143-53.
36. Adam J, Hatipoglu E, O'Flaherty L, et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 2011;20:524-37.
37. Zhao S, Lin Y, Xu W, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 2009;324:261-5.
38. Koivunen P, Lee S, Duncan CG, et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 2012;483:484-8.
39. Tarhonskaya H, Rydzik AM, Leung IK, et al. Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases. Nat Commun 2014;5:3423.
40. Berger SL, Kouzarides T, Shiekhattar R, et al. An operational definition of epigenetics. Genes Dev 2009;23:781-3.
41. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000;403:41-5.
42. Kouzarides T. Chromatin modifications and their function. Cell 2007;128:693-705.
43. Allis CD, Berger SL, Cote J, et al. New nomenclature for chromatin-modifying enzymes. Cell 2007;131:633-6.
44. Li B, Carey M, Workman JL. The role of chromatin during transcription. Cell 2007;128:707-19.
45. Barski A, Cuddapah S, Cui K, et al High-resolution profiling of histone methylations in the human genome. Cell 2007;129:823-37.
46. Zentner GE, Henikoff S. Regulation of nucleosome dynamics by histone modifications. Nat Struct Mol Biol 2013;20:259-66.
47. Esteller M. Epigenetics in cancer. N Engl J Med 2008;358:1148-59.
48. Kooistra SM, Helin K. Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol 2012;13:297-311.
49. Chervona Y, Costa M. The control of histone methylation and gene expression by oxidative stress, hypoxia, and metals. Free Radic Biol Med 2012;53:1041-7.
50. Xia X, Lemieux ME, Li W, et al. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci USA 2009;106:4260-5.
51. Smith EH, Janknecht R, Maher LJ, III. Succinate inhibition of alpha-ketoglutarate-dependent enzymes in a yeast model of paraganglioma. Hum Mol Genet 2007;16:3136-48.
52. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011;19:17-30.
53. Chowdhury R, Yeoh KK, Tian YM, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep 2011;12:463-9.
54. Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012;483:474-8.
55. Cervera AM, Bayley JP, Devilee P, et al. Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells. Mol Cancer 2009;8:89.
56. Xiao M, Yang H, Xu W, et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 2012;26:1326-38.
57. Letouzé E, Martinelli C, Loriot C, et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 2013;23:739-52.
58. Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 2009;10:295-304.
59. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet 2006;7:21-33.
60. Fraga MF, Herranz M, Espada J, et al. A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors. Cancer Res 2004;64:5527-34.
61. Rodriguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med 2011;17:330-9.
62. Sakai T, Toguchida J, Ohtani N, et al. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet 1991;48:880-8.
63. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003;349:2042-54.
64. Wu H, Zhang Y. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 2011;25:2436-52.
65. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009;324:930-5.
66. Ito S, D'Alessio AC, Taranova OV, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010;466:1129-33.
67. Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012;483:479-83.
68. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010;18:553-67.
69. Killian JK, Kim SY, Miettinen M, et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov 2013;3:648-57.
70. Lu C, Venneti S, Akalin A, et al. Induction of sarcomas by mutant IDH2. Genes Dev 2013;27:1986-98.
71. Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010;17:510-22.
72. Hinoue T, Weisenberger DJ, Lange CP, et al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res 2012;22:271-82.
73. Ohm JE, McGarvey KM, Yu X, et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 2007;39:237-42.
74. Costello JF, Fruhwald MC, Smiraglia DJ, et al. Aberrant CpG-island methylation has nonrandom and tumour-type-specific patterns. Nat Genet 2000;24:132-8.
75. Tarayrah L, Chen X. Epigenetic regulation in adult stem cells and cancers. Cell Biosci 2013;3:41.
76. Grassian AR, Lin F, Barrett R, et al. Isocitrate dehydrogenase (IDH) mutations promote a reversible ZEB1/microRNA (miR) - 200-dependent epithelial-mesenchymal transition (EMT). J Biol Chem 2012;287:42180-94.
77. Geli J, Kiss N, Karimi M, et al. Global and regional CpG methylation in pheochromocytomas and abdominal paragangliomas: association to malignant behavior. Clin Cancer Res 2008;14:2551-9.
78. Jin SG, Jiang Y, Qiu R, et al. 5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res 2011;71:7360-5.
79. Haffner MC, Chaux A, Meeker AK, et al. Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget 2011;2:627-37.
80. Li W, Liu M. Distribution of 5-hydroxymethylcytosine in different human tissues. J Nucleic Acids 2011;2011:870726.
81. Tan L, Shi YG. Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 2012;139:1895-902.
82. Lian CG, Xu Y, Ceol C, et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 2012;150:1135-46.
83. Orr BA, Haffner MC, Nelson WG, et al. Decreased 5-hydroxymethylcytosine is associated with neural progenitor phenotype in normal brain and shorter survival in malignant glioma. PLoS One 2012;7:e41036.
84. Pollyea DA, Kohrt HE, Zhang B, et al. 2-Hydroxyglutarate in IDH mutant acute myeloid leukemia: predicting patient responses, minimal residual disease and correlations with methylcytosine and hydroxymethylcytosine levels. Leuk Lymphoma 2013;54:408-10.
85. Kraus TF, Globisch D, Wagner M, et al. Low values of 5-hydroxymethylcytosine (5hmC), the "sixth base," are associated with anaplasia in human brain tumors. Int J Cancer 2012;131:1577-90.
86. Kim YH, Pierscianek D, Mittelbronn M, et al. TET2 promoter methylation in low-grade diffuse gliomas lacking IDH1/2 mutations. J Clin Pathol 2011;64:850-2.
87. Muller T, Gessi M, Waha A, et al. Nuclear exclusion of TET1 is associated with loss of 5-hydroxymethylcytosine in IDH1 wild-type gliomas. Am J Pathol 2012;181:675-83.
88. Rohle D, Popovici-Muller J, Palaskas N, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 2013;340:626-30.
89. Losman JA, Looper RE, Koivunen P, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013;339:1621-5.
90. Loenarz C, Schofield CJ. Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol 2008;4:152-6.
91. McDonough MA, Loenarz C, Chowdhury R, et al. Structural studies on human 2-oxoglutarate dependent oxygenases. Curr Opin Struct Biol 2010;20:659-72.
92. Rose NR, McDonough MA, King ON, et al. Inhibition of 2-oxoglutarate dependent oxygenases. Chem Soc Rev 2011;40:4364-97.
93. Dinchuk JE, Focht RJ, Kelley JA, et al. Absence of post-translational aspartyl beta-hydroxylation of epidermal growth factor domains in mice leads to developmental defects and an increased incidence of intestinal neoplasia. J Biol Chem 2002;277:12970-7.
94. Webby CJ, Wolf A, Gromak N, et al. Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science 2009;325:90-3.
95. Ge W, Wolf A, Feng T, et al. Oxygenase-catalyzed ribosome hydroxylation occurs in prokaryotes and humans. Nat Chem Biol 2012;8:960-2.
96. Kivirikko KI, Myllyla R. Post-translational processing of procollagens. Ann N Y Acad Sci 1985;460:187-201.
97. Myllyharju J, Kivirikko KI. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet 2004;20:33-43.
98. Martins VL, Vyas JJ, Chen M, et al. Increased invasive behaviour in cutaneous squamous cell carcinoma with loss of basement-membrane type VII collagen. J Cell Sci 2009;122:1788-99.
99. Sasaki M, Knobbe CB, Itsumi M, et al. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev 2012;26:2038-49.
100. Sedgwick B, Bates PA, Paik J, et al. Repair of alkylated DNA: recent advances. DNA Repair (Amst) 2007;6:429-42.
101. Aas PA, Otterlei M, Falnes PO, et al. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature 2003;421:859-63.
102. Ringvoll J, Nordstrand LM, Vagbo CB, et al. Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA. EMBO J 2006;25:2189-98.
103. Lee SY, Luk SK, Chuang CP, et al. TP53 regulates human AlkB homologue 2 expression in glioma resistance to Photofrin-mediated photodynamic therapy. Br J Cancer 2010;103:362-9.
104. SongTao Q, Lei Y, Si G, et al. IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Sci 2012;103:269-73.
105. Lee S, Nakamura E, Yang H, et al. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 2005;8:155-67.
106. Bishop T, Gallagher D, Pascual A, et al. Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice. Mol Cell Biol 2008;28:3386-400.
107. Schlisio S, Kenchappa RS, Vredeveld LC, et al. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev 2008;22:884-93.
108. Adachi H, Fujiwara Y, Ishii N. Effects of oxygen on protein carbonyl and aging in Caenorhabditis elegans mutants with long (age-1) and short (mev-1) life spans. J Gerontol A Biol Sci Med Sci 1998;53:B240-B244.
109. Sosa V, Moline T, Somoza R, et al. Oxidative stress and cancer: an overview. Ageing Res Rev 2013;12:376-90.
110. Ishii T, Yasuda K, Akatsuka A, et al. A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis. Cancer Res 2005;65:203-9.
111. Slane BG, Aykin-Burns N, Smith BJ, et al. Mutation of succinate dehydrogenase subunit C results in increased O2.-, oxidative stress, and genomic instability. Cancer Res 2006;66:7615-20.
112. DeNicola GM, Karreth FA, Humpton TJ, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011;475:106-9.
113. Mitsuishi Y, Taguchi K, Kawatani Y, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 2012;22:66-79.
114. Alderson NL, Wang Y, Blatnik M, et al. S-(2-Succinyl)cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate. Arch Biochem Biophys 2006;450:1-8.
115. Ooi A, Wong JC, Petillo D, et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 2011;20:511-23.
116. Bardella C, El-Bahrawy M, Frizzell N, et al. Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J Pathol 2011;225:4-11.
117. Jimenez C, Rohren E, Habra MA, et al. Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. Curr Oncol Rep 2013;15:356-71.
118. Lv S, Teugels E, Sadones J, et al. Correlation between IDH1 gene mutation status and survival of patients treated for recurrent glioma. Anticancer Res 2011;31:4457-63.
119. Favier J, Igaz P, Burnichon N, et al. Rationale for anti-angiogenic therapy in pheochromocytoma and paraganglioma. Endocr Pathol 2012;23:34-42.
120. Tuthill M, Barod R, Pyle L, et al. A report of succinate dehydrogenase B deficiency associated with metastatic papillary renal cell carcinoma: successful treatment with the multi-targeted tyrosine kinase inhibitor sunitinib. BMJ Case Rep 2009;2009: bcr08.2008.0732.
121. Joshua AM, Ezzat S, Asa SL, et al. Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/pheochromocytoma. J Clin Endocrinol Metab 2009;94:5-9.
122. Hahn NM, Reckova M, Cheng L, et al. Patient with malignant paraganglioma responding to the multikinase inhibitor sunitinib malate. J Clin Oncol 2009;27:460-3.
123. Jimenez C, Cabanillas ME, Santarpia L, et al. Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors. J Clin Endocrinol Metab 2009;94:386-91.
124. Nemoto K, Miura T, Shioji G, et al. Sunitinib treatment for refractory malignant pheochromocytoma. Neuro Endocrinol Lett 2012;33:260-4.
125. Ayala-Ramirez M, Chougnet CN, Habra MA, et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab 2012;97:4040-50.
126. Hadoux J, Favier J, Scoazec JY, et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma and paraganglioma. Int J Cancer 2014 Apr 18. doi: 10.1002/ijc.28913.
127. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell 2012;150:12-27.
128. O'Connor OA, Heaney ML, Schwartz L, et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 2006;24:166-73.
129. Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 2009;27:5410-17.
130. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10:223-32.
131. Gurion R, Vidal L, Gafter-Gvili A, et al. 5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome - a systematic review and meta-analysis. Haematologica 2010;95:303-10.
132. Tsai HC, Li H, Van Neste L, et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 2012;21:430-46.
133. Ren J, Singh BN, Huang Q, et al. DNA hypermethylation as a chemotherapy target. Cell Signal 2011;23:1082-93.
134. Beumer JH, Parise RA, Newman EM, et al. Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine (FdCyd) and its cytotoxic metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU). Cancer Chemother Pharmacol 2008;62:363-8.
135. Turcan S, Fabius AW, Borodovsky A, et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT Inhibitor Decitabine. Oncotarget 2013;4:1729-36.
136. Juergens RA, Wrangle J, Vendetti FP, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov 2011;1:598-607.
137. Matsumoto K, Obara N, Ema M, et al. Antitumor effects of 2-oxoglutarate through inhibition of angiogenesis in a murine tumor model. Cancer Sci 2009;100:1639-47.
138. MacKenzie ED, Selak MA, Tennant DA, et al. Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol 2007;27:3282-9.
139. Tennant DA, Frezza C, MacKenzie ED, et al. Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. Oncogene 2009;28:4009-21.
140. Monfort A, Wutz A. Breathing-in epigenetic change with vitamin C. EMBO Rep 2013;14:337-46.
141. Minor EA, Court BL, Young JI, et al. Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine. J Biol Chem 2013;288:13669-74.
142. Chen J, Guo L, Zhang L, et al. Vitamin C modulates TET1 function during somatic cell reprogramming. Nat Genet 2013;45:1504-9.
143. Blaschke K, Ebata KT, Karimi MM, et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 2013;500:222-6.
144. Padayatty SJ, Sun AY, Chen Q, et al. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One 2010;5:e11414.
145. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci USA 1978;75:4538-42.
146. Gonzalez MJ, Miranda-Massari JR, Mora EM, et al. Orthomolecular oncology review: ascorbic acid and cancer 25 years later. Integr Cancer Ther 2005;4:32-44.
147. Park S. The effects of high concentrations of vitamin C on cancer cells. Nutrients 2013;5:3496-505.
148. Wang F, Travins J, DeLaBarre B, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013;340:622-6.
149. Pastor WA, Aravind L, Rao A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol 2013;14:341-56.