The Epigenetics of Cancer in Children

Abstract

Malignant tumors of childhood represent a rather heterogeneous group of neoplasms originating from virtually any anatomical structure. Despite major improvements in the clinical management including timely diagnosis, advanced supportive care and refined multimodality treatment, prognosis remains grim for certain risk groups. Aberrant epigenetic regulation, i.e. changes in gene transcription not due to DNA sequence alterations, is now increasingly recognized as a fundamental process in malignant transformation, tumor progression and drug resistance. The molecular mechanisms involve aberrant activity of enzymes controlling the packaging and transcriptional regulation of the genome. Two major protein families are involved in this process, DNA methyltransferases and histone deacetylases. With the availability of small molecule inhibitors targeting the aberrant epigenetic machinery in cancer cells, these compounds are evaluated in several clinical trials.

Zusammenfassung

Trotz großer Fortschritte in der Diagnostik und Therapie von Krebserkrankungen im Kindes- und Jugendalter ist die Prognose insbesondere von fortgeschrittenen Tumoren weiterhin ungünstig. In den letzten Jahren hat sich gezeigt, dass fehlgesteuerte epigenetische Regulationsmechanismen eine fundamentale Rolle in der malignen Transformation, Progression und Therapieresistenz von Tumoren spielen. Unter „Epigenetik” versteht man den erblichen Aktivitätszustand von Genen, dessen Information unabhängig von der Basensequenz der DNA ist. Hierbei spielen die DNA-Methyltransferasen und die Histon-Deacetylasen eine zentrale Rolle. Sie regulieren den „Verpackungszustand” des menschlichen Genoms und sind an der Kontrolle des Expressionsprofils von Genen in einer Zelle beteiligt. In malignen Geweben sind diese Enzymfamilien pathologisch aktiv. Durch kleinmolekulare Inhibitoren können DNA-Methyltransferasen und Histon-Deacetylasen gehemmt werden und dadurch anti-tumorale Wirkungen entfalten.

Key words

epigenetics - DNMT - HDAC - inhibitors - pediatric oncology

Schlüsselwörter

Epigenetik - DNMT - HDAC - Inhibitoren - pädiatrische Onkologie

Literatur

• 1 Antequera F, Bird A. Number of CpG islands and genes in human and mouse.  Proc Natl Acad Sci USA. 1993;  90 11995-11999
• 2 Aparicio A, Eads CA, Leong LA. et al . Phase I trial of continuous infusion 5-aza-2′-deoxycytidine.  Cancer Chemother Pharmacol. 2003;  51 231-239
• 3 Balch C, Montgomery JS, Paik HI. et al . New anti-cancer strategies: epigenetic therapies and biomarkers.  Front Biosci. 2005;  10 1897-1931
• 4 Bali P, Pranpat M, Bradner J. et al . Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors.  J Biol Chem. 2005;  280 26729-26734
• 5 Bayani J, Selvarajah S, Maire G. et al . Genomic mechanisms and measurement of structural and numerical instability in cancer cells.  Semin Cancer Biol. 2007;  17 5-18
• 6 Bhalla KN. Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies.  J Clin Oncol. 2005;  23 3971-3993
• 7 Bird A. DNA methylation patterns and epigenetic memory.  Genes Dev. 2002;  16 6-21
• 8 Bjornsson HT, Brown LJ, Fallin MD. et al . Epigenetic specificity of loss of imprinting of the IGF2 gene in Wilms tumors.  J Natl Cancer Inst. 2007;  99 1270-1273 , Epub 2007 Aug 1278
• 9 Blumenschein G, Lu G, Kies M. et al . Phase II clinical trial of suberoylanilide hydroxamic acid (SAHA) in patients with recurrent and/or metastatic head and neck cancer(SCCHN).  Invest New Drugs. 2008;  26 81-87
• 10 Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors.  Nat Rev Drug Discov. 2006;  5 769-784
• 11 Brueckner B, Boy RG, Siedlecki P. et al . Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases.  Cancer Res. 2005;  65 6305-6311
• 12 Byrd JC, Marcucci G, Parthun MR. et al . A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia.  Blood. 2005;  105 959-967
• 13 Cameron EE, Bachman KE, Myohanen S. et al . Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer.  Nat Genet. 1999;  21 103-107
• 14 Chavez-Blanco A, Segura-Pacheco B, Perez-Cardenas E. et al . Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer.  A phase I study. Mol Cancer. 2005;  4 22
• 15 Cheng JC, Matsen CB, Gonzales FA. et al . Inhibition of DNA methylation and reactivation of silenced genes by zebularine.  J Natl Cancer Inst. 2003;  95 399-409
• 16 Cheng JC, Yoo CB, Weisenberger DJ. et al . Preferential response of cancer cells to zebularine.  Cancer Cell. 2004;  6 151-158
• 17 Cinatl Jr J, Cinatl J, Scholz M. et al . Antitumor activity of sodium valproate in cultures of human neuroblastoma cells.  Anticancer Drugs. 1996;  7 766-773
• 18 Cooper DN, Krawczak M. Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomes.  Hum Genet. 1989;  83 181-188
• 19 Costello JF, Fruhwald MC, Smiraglia DJ. et al . Aberrant CpG-island methylation has non-random and tumour-type-specific patterns.  Nat Genet. 2000;  24 132-138
• 20 Davis AJ, Gelmon KA, Siu LL. et al . Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks.  Invest New Drugs. 2003;  21 85-97
• 21 Deubzer HE, Ehemann V, Kulozik AE. et al . Anti-neuroblastoma activity of Helminthosporium carbonum (HC)-toxin is superior to that of other differentiating compounds in vitro.  Cancer Lett. 2008;  264 21-28
• 22 Deubzer HE, Ehemann V, Westermann F. et al . Inhibiting histone deacetylases in neuroblastoma.  Klin Padiatr. 2007;  219 183
• 23 Deubzer HE, Ehemann V, Westermann F. et al . Histone deacetylase inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of neuroblastoma cells.  Int J Cancer. 2008;  122 1891-1900
• 24 Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives.  Mol Cancer Res. 2007;  5 981-989
• 25 Donson AM, Addo-Yobo SO, Handler MH. et al . MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma.  Pediatr Blood Cancer. 2007;  48 403-407
• 26 Ebinger M, Senf L, Scheurlen W. Risk stratification in medulloblastoma: screening for molecular markers.  Klin Padiatr. 2006;  218 139-142
• 27 Eden A, Gaudet F, Waghmare A. et al . Chromosomal instability and tumors promoted by DNA hypomethylation.  Science. 2003;  300 455
• 28 Ehrlich M. DNA methylation in cancer: too much, but also too little.  Oncogene. 2002;  21 5400-5413
• 29 Einsiedel HG, Kawan L, Eckert C. et al . Histone deacetylase inhibitors have antitumor activity in two NOD/SCID mouse models of B-cell precursor childhood acute lymphoblastic leukemia.  Leukemia. 2006;  20 1435-1436
• 30 Esteller M. Epigenetics in cancer.  N Engl J Med. 2008;  358 1148-1159
• 31 Esteller M. Aberrant DNA methylation as a cancer-inducing mechanism.  Annu Rev Pharmacol Toxicol. 2005;  45 629-656
• 32 Feinberg AP. Imprinting of a genomic domain of 11p15 and loss of imprinting in cancer: an introduction.  Cancer Res. 1999;  59 1743s-1746s
• 33 Feinberg AP. Phenotypic plasticity and the epigenetics of human disease.  Nature. 2007;  447 433-440
• 34 Feinberg AP. Epigenetics at the epicenter of modern medicine.  Jama. 2008;  299 1345-1350
• 35 Fouladi M, Furman WL, Chin T. et al . Phase I study of depsipeptide in pediatric patients with refractory solid tumors: a Children's Oncology Group report.  J Clin Oncol. 2006;  24 3678-3685
• 36 Fraga MF, Ballestar E, Villar-Garea A. et al . Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer.  Nat Genet. 2005;  37 391-400
• 37 Frühwald MC. DNA methylation patterns in cancer: novel prognostic indicators?.  Am J Pharmacogenomics. 2003;  3 245-260
• 38 Frühwald MC, O’Dorisio MS, Dai Z. et al . Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas- Implications for tumor biology and potential clinical utility.  Oncogene. 2001;  20 5033-5042
• 39 Frühwald MC, O’Dorisio MS, Dai Z. et al . Aberrant hypermethylation of the major breakpoint cluster region in 17p11.2 in medulloblastomas but not supratentorial PNETs.  Genes, Chromosomes & Cancer. 2001;  30 38-47
• 40 Frühwald MC, O’Dorisio MS, Smith L. et al . Hypermethylation as a potential prognostic factor and a clue to a better understanding of the molecular pathogenesis of medulloblastoma – results of a genomewide methylation scan.  Klin Padiatr. 2001;  213 197-203
• 41 Frühwald MC, Plass C. Global and gene-specific methylation patterns in cancer: aspects of tumor biology and clinical potential.  Mol Genet Metab. 2002;  75 1-16
• 42 Fujita N, Watanabe S, Ichimura T. et al . Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression.  J Biol Chem. 2003;  278 24132-24138
• 43 Fukuzawa R, Anaka M, Heathcott R. et al . Wilms tumour histology is determined by distinct types of precursor lesions and not epigenetic changes.  J Pathol. 2008;  215 377-387
• 44 Fukuzawa R, Reeve AE. Molecular pathology and epidemiology of nephrogenic rests and Wilms tumors.  J Pediatr Hematol Oncol. 2007;  29 589-594
• 45 Furchert SE, Lanvers-Kaminsky C, Jurgens H. et al . Inhibitors of histone deacetylases as potential therapeutic tools for high-risk embryonal tumors of the nervous system of childhood.  Int J Cancer. 2007;  120 1787-1794
• 46 Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B. et al . Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia.  Blood. 2006;  108 3271-3279
• 47 Gardiner-Garden M, Frommer M. CpG islands in vertebrate genomes.  J Mol Biol. 1987;  196 261-282
• 48 Gaudet F, Hodgson JG, Eden A. et al . Induction of tumors in mice by genomic hypomethylation.  Science. 2003;  300 489-492
• 49 Glaser KB, Li J, Staver MJ. et al . Role of class I and class II histone deacetylases in carcinoma cells using siRNA.  Biochem Biophys Res Commun. 2003;  310 529-536
• 50 Gore SD, Baylin S, Sugar E. et al . Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms.  Cancer Res. 2006;  66 6361-6369
• 51 Gottlicher M, Minucci S, Zhu P. et al . Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.  Embo J. 2001;  20 6969-6978
• 52 Graham C, Tucker C, Creech J. et al . Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo.  Clin Cancer Res. 2006;  12 223-234
• 53 Grant S, Easley C, Kirkpatrick P. Vorinostat.  Nat Rev Drug Discov. 2007;  6 21-22
• 54 Haggarty SJ, Koeller KM, Wong JC. et al . Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation.  Proc Natl Acad Sci USA. 2003;  100 4389-4394
• 55 Hahnen E, Eyupoglu IY, Brichta L. et al . In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy.  J Neurochem. 2006;  98 193-202
• 56 Harms D, Zahn S, Göbel U. et al . Pathology and molecular biology of teratomas in childhood and adolescence.  Klin Padiatr. 2006;  218 296-302
• 57 Hegi ME, Diserens AC, Gorlia T. et al . MGMT gene silencing and benefit from temozolomide in glioblastoma.  N Engl J Med. 2005;  352 997-1003
• 58 Hitchins MP, Wong JJ, Suthers G. et al . Inheritance of a cancer-associated MLH1 germ-line epimutation.  N Engl J Med. 2007;  356 697-705
• 59 Hockly E, Richon VM, Woodman B. et al . Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease.  Proc Natl Acad Sci USA. 2003;  100 2041-2046
• 60 Holleran JL, Parise RA, Joseph E. et al . Plasma pharmacokinetics, oral bioavailability, and interspecies scaling of the DNA methyltransferase inhibitor, zebularine.  Clin Cancer Res. 2005;  11 3862-3868
• 61 Issa JP, Garcia-Manero G, Giles FJ. et al . Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies.  Blood. 2004;  103 1635-1640
• 62 Issa JP, Ottaviano YL, Celano P. et al . Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon.  Nat Genet. 1994;  7 536-540
• 63 Jaboin J, Wild J, Hamidi H. et al . MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors.  Cancer Res. 2002;  62 6108-6115
• 64 Jelinic P, Shaw P. Loss of imprinting and cancer.  J Pathol. 2007;  211 261-268
• 65 Jones PA, Baylin SB. The epigenomics of cancer.  Cell. 2007;  128 683-692
• 66 Kantarjian HM, O’Brien S, Cortes J. et al . Results of decitabine (5-aza-2′deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia.  Cancer. 2003;  98 522-528
• 67 Kantarjian H, Oki Y, Garcia-Manero G. et al . Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia.  Blood. 2007;  109 52-57
• 68 Kelly WK, O’Connor O A, Krug LM. et al . Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients With Advanced Cancer.  J Clin Oncol. 2005;  16 16
• 69 Kelly WK, Richon VM, O’Connor O. et al . Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously.  Clin Cancer Res. 2003;  9 3578-3588
• 70 Keshelava N, Davicioni E, Wan Z. et al . Histone deacetylase 1 gene expression and sensitization of multidrug-resistant neuroblastoma cell lines to cytotoxic agents by depsipeptide.  J Natl Cancer Inst. 2007;  99 1107-1119
• 71 Khan N, Jeffers M, Kumar S. et al . Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors.  Biochem J. 2008;  409 581-589
• 72 Knudson AG. Two genetic hits (more or less) to cancer.  Nat Rev Cancer. 2001;  1 157-162
• 73 Kopelovich L, Crowell JA, Fay JR. The epigenome as a target for cancer chemoprevention.  J Natl Cancer Inst. 2003;  95 1747-1757
• 74 Kornblith AB, Herndon 2nd JE, Silverman LR. et al . Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study.  J Clin Oncol. 2002;  20 2441-2452
• 75 Kraker AJ, Mizzen CA, Hartl BG. et al . Modulation of histone acetylation by [4-(acetylamino)-N-(2-amino-phenyl) benzamide] in HCT-8 colon carcinoma.  Mol Cancer Ther. 2003;  2 401-408
• 76 Kramer OH, Zhu P, Ostendorff HP. et al . The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2.  Embo J. 2003;  22 3411-3420
• 77 Laird PW. Cancer epigenetics.  Hum Mol Genet. 2005;  14 ((Spec No 1)) R65-R76
• 78 Li Y, Zhang X, Polakiewicz RD. et al . HDAC6 is required for EGF-induced beta -catenin nuclear localization.  J Biol Chem. 2008;  283 12686-12690
• 79 Lin X, Asgari K, Putzi MJ. et al . Reversal of GSTP1 CpG island hypermethylation and reactivation of pi-class glutathione S-transferase (GSTP1) expression in human prostate cancer cells by treatment with procainamide.  Cancer Res. 2001;  61 8611-8616
• 80 Lindsey JC, Lusher ME, Anderton JA. et al . Identification of tumour-specific epigenetic events in medulloblastoma development by hypermethylation profiling.  Carcinogenesis. 2004;  25 661-668
• 81 Lujambio A, Ropero S, Ballestar E. et al . Genetic unmasking of an epigenetically silenced microRNA in human cancer cells.  Cancer Res. 2007;  67 1424-1429
• 82 Lusher ME, Lindsey JC, Latif F. et al . Biallelic epigenetic inactivation of the RASSF1A tumor suppressor gene in medulloblastoma development.  Cancer Res. 2002;  62 5906-5911
• 83 Lyko F, Brown R. DNA methyltransferase inhibitors and the development of epigenetic cancer therapies.  J Natl Cancer Inst. 2005;  97 1498-1506
• 84 Mack GS. Epigenetic cancer therapy makes headway.  J Natl Cancer Inst. 2006;  98 1443-1444
• 85 Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer.  Nat Rev Cancer. 2006;  6 38-51
• 86 Momparler RL, Rivard GE, Gyger M. Clinical trial on 5-aza-2′-deoxycytidine in patients with acute leukemia.  Pharmacol Ther. 1985;  30 277-286
• 87 Momparler RL, Cote S, Eliopoulos N. Pharmacological approach for optimization of the dose schedule of 5-Aza- 2′-deoxycytidine (Decitabine) for the therapy of leukemia.  Leukemia. 1997;  11 ((Suppl 1)) S1-S6
• 88 Mottet D, Bellahcene A, Pirotte S. et al . Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis.  Circ Res. 2007;  101 1237-1246
• 89 Mühlisch J, Bajanowski T, Rickert CH. et al . Frequent but borderline methylation of p16 (INK4a) and TIMP3 in medulloblastoma and sPNET revealed by quantitative analyses.  J Neurooncol. 2007;  83 17-29
• 90 Mühlisch J, Schwering A, Grotzer M. et al . Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood.  Oncogene. 2006;  25 1111-1117
• 91 Murrell A, Rakyan VK, Beck S. From genome to epigenome.  Hum Mol Genet. 2005;  14 ((Spec No 1)) R3-R10
• 92 Oberndorfer S, Piribauer M, Marosi C. et al . P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy.  J Neurooncol. 2005;  72 255-260
• 93 Oehme I, Deubzer HE, Wegener D. et al . Histone deacetylase 8 in neuroblastoma tumorigenesis.  Clin Cancer Res in press. 2008; 
• 94 Parham DM, Ellison DA. Rhabdomyosarcomas in adults and children: an update.  Arch Pathol Lab Med. 2006;  130 1454-1465
• 95 Park JH, Kim SH, Choi MC. et al . Class II histone deacetylases play pivotal roles in heat shock protein 90-mediated proteasomal degradation of vascular endothelial growth factor receptors.  Biochem Biophys Res Commun. 2008;  368 318-322
• 96 Pauer LR, Olivares J, Cunningham C. et al . Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors.  Cancer Invest. 2004;  22 886-896
• 97 Pfeifer GP, You YH, Besaratinia A. Mutations induced by ultraviolet light.  Mutat Res. 2005;  571 19-31
• 98 Piekarz RL, Robey R, Sandor V. et al . Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report.  Blood. 2001;  98 2865-2868
• 99 Pohlmann P, DiLeone LP, Cancella AI. et al . Phase II trial of cisplatin plus decitabine, a new DNA hypomethylating agent, in patients with advanced squamous cell carcinoma of the cervix.  Am J Clin Oncol. 2002;  25 496-501
• 100 Prakash S, Foster BJ, Meyer M. et al . Chronic oral administration of CI-994: a phase 1 study.  Invest New Drugs. 2001;  19 1-11
• 101 Qian DZ, Kachhap SK, Collis SJ. et al . Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha.  Cancer Res. 2006;  66 8814-8821
• 102 Rollins RA, Haghighi F, Edwards JR. et al . Large-scale structure of genomic methylation patterns.  Genome Res. 2006;  16 157-163
• 103 Ryan QC, Headlee D, Acharya M. et al . Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma.  J Clin Oncol. 2005;  23 3912-3922
• 104 Saito A, Yamashita T, Mariko Y. et al . A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors.  Proc Natl Acad Sci USA. 1999;  96 4592-4597
• 105 Sandor V, Bakke S, Robey RW. et al . Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms.  Clin Cancer Res. 2002;  8 718-728
• 106 Schlosser S, Frühwald MC. Epigenetic mechanisms in the development of malignancies of the central nervous system (CNS). In, Trends in Brain Cancer Research. San Francisco: Novaeditorial Publishers 2008 in press
• 107 Segura-Pacheco B, Trejo-Becerril C, Perez-Cardenas E. et al . Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy.  Clin Cancer Res. 2003;  9 1596-1603
• 108 Shan B, Yao TP, Nguyen HT. et al . Requirement of HDAC6 for TGF-beta 1-induced epithelial-mesenchymal transition.  J Biol Chem. 2008;  283 21065-21073
• 109 Singal R, Ginder GD. DNA methylation.  Blood. 1999;  93 4059-4070
• 110 Sonnemann J, Kumar KS, Heesch S. et al . Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells.  Int J Oncol. 2006;  28 755-766
• 111 Soriano AO, Yang H, Faderl S. et al . Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome.  Blood. 2007;  110 2302-2308
• 112 Sparago A, Russo S, Cerrato F. et al . Mechanisms causing imprinting defects in familial Beckwith-Wiedemann syndrome with Wilms’ tumour.  Hum Mol Genet. 2007;  16 254-264 , Epub 2006 Dec 2011
• 113 Suter CM, Martin DI, Ward RL. Germline epimutation of MLH1 in individuals with multiple cancers.  Nat Genet. 2004;  36 497-501 , Epub 2004 Apr 2004
• 114 Tabe Y, Jin L, Contractor R. et al . Novel role of HDAC inhibitors in AML1/ETO AML cells: activation of apoptosis and phagocytosis through induction of annexin A1.  Cell Death Differ. 2007;  14 1443-1456
• 115 Takai D, Jones PA. Comprehensive analysis of CpG islands in human chromosomes 21 and 22.  Proc Natl Acad Sci USA. 2002;  99 3740-3745
• 116 Ting AH, MacGarvey KM, Baylin SB. The cancer epigenome–components and functional correlates.  Genes Dev. 2006;  20 3215-3231
• 117 Turker MS, Bestor TH. Formation of methylation patterns in the mammalian genome.  Mutat Res. 1997;  386 119-130
• 118 Ushijima T, Okochi-Takada E. Aberrant methylations in cancer cells: where do they come from?.  Cancer Sci. 2005;  96 206-211
• 119 Vanhaecke T, Papeleu P, Elaut G. et al . Trichostatin A-like hydroxamate histone deacetylase inhib`itors as therapeutic agents: toxicological point of view.  Curr Med Chem. 2004;  11 1629-1643
• 120 Villar-Garea A, Fraga MF, Espada J. et al . Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells.  Cancer Res. 2003;  63 4984-4989
• 121 Vorinostat With or Without Isotretinoin in Treating Young Patients With Recurrent or Refractory Solid Tumors, Lymphoma, or Leukemia. http://wwwclinicaltrialsgov/ct/show/NCT00217412?order=1 , Children's Oncology Group (NCT00217412)
• 122 Waddington CH. The Epigenotype.  Endeavour. 1942;  1 18-2053 , . Weichert W, Roske A, Gekeler V et al. Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis. Lancet Oncol 2008;9:139–148.
• 123 Watt PM, Kumar R, Kees UR. Promoter demethylation accompanies reactivation of the HOX11 proto-oncogene in leukemia.  Genes Chromosomes Cancer. 2000;  29 371-377
• 124 Wegener D, Deubzer HE, Oehme I. et al . A novel HDAC inhibitor identified in the screening of a compound library id effective in neuroblastoma cells.  Klin Padiatr. 2007;  219 195
• 125 Weichert W, Roske A, Gekeler V. et al . Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis.  Lancet Oncol. 2008;  9 139-148
• 126 Weichert W, Roske A, Niesporek S. et al . Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: specific role of class I histone deacetylases in vitro and in vivo.  Clin Cancer Res. 2008;  14 1669-1677
• 127 Witt O, Deubzer H, Milde T. et al . HDAC family: what are the cancer relevant targets?.  Cancer Lett in press. 2008; 
• 128 Witt O, Kanbach K, Krenz K. et al . Induction of tumor cell differentiation by histone-deacetylase inhibitors.  Klin Padiatr. 2002;  214 257
• 129 Witt O, Monkemeyer S, Ronndahl G. et al . Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin.  Blood. 2003;  101 2001-2007
• 130 Witt O, Sand K, Pekrun A. Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways.  Blood. 2000;  95 2391-2396
• 131 Witt O, Schweigerer L, Driever PH. et al . Valproic acid treatment of glioblastoma multiforme in a child.  Pediatr Blood Cancer. 2004;  43 181
• 132 Yoon JH, Smith LE, Feng Z. et al . Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers.  Cancer Res. 2001;  61 7110-7117

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