Sự phát sinh bệnh lý phân tử đang nổi lên của neuroblastoma: Những tác động đối với việc đánh giá rủi ro và liệu pháp nhắm mục tiêu được cải thiện

Schwab M, Westermann F, Hero B, Berthold F: Neuro blastoma: biology and molecular and chromosomal pathology. Lancet Oncol. 2003, 4: 472-480. 10.1016/S1470-2045(03)01166-5 Brodeur GM: Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003, 3: 203-216. 10.1038/nrc1014 Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, Faldum A, Hero B, Iehara T, Machin D, Mosseri V, Simon T, Garaventa A, Castel V, Matthay KK: The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009, 27: 289-297. 10.1200/JCO.2008.16.6785 Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, Kaneko M, London WB, Matthay KK, Nuchtern JG, von Schweinitz D, Simon T, Cohn SL, Pearson AD: The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol. 2009, 27: 298-303. 10.1200/JCO.2008.16.6876 Ambros PF, Ambros IM, Brodeur GM, Haber M, Khan J, Nakagawara A, Schleiermacher G, Speleman F, Spitz R, London WB, Cohn SL, Pearson AD, Maris JM: International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer. 2009, 100: 1471-1482. 10.1038/sj.bjc.6605014 Bagatell R, Rumcheva P, London WB, Cohn SL, Look AT, Brodeur GM, Frantz C, Joshi V, Thorner P, Rao PV, Castleberry R, Bowman LC: Outcomes of children with intermediate-risk neuroblastoma after treatment stratified by MYCN status and tumor cell ploidy. J Clin Oncol. 2005, 23: 8819-8827. 10.1200/JCO.2004.00.2931 George RE, London WB, Cohn SL, Maris JM, Kretschmar C, Diller L, Brodeur GM, Castleberry RP, Look AT: Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol. 2005, 23: 6466-6473. 10.1200/JCO.2005.05.582 Look AT, Hayes FA, Shuster JJ, Douglass EC, Castleberry RP, Bowman LC, Smith EI, Brodeur GM: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1991, 9: 581-591. Kaneko Y, Knudson AG: Mechanism and relevance of ploidy in neuroblastoma. Genes Chromosomes Cancer. 2000, 29: 89-95. 10.1002/1098-2264(2000)9999:9999<::AID-GCC1021>3.0.CO;2-Y Schwab M, Varmus HE, Bishop JM, Grzeschik KH, Naylor SL, Sakaguchi AY, Brodeur G, Trent J: Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc. Nature. 1984, 308: 288-291. 10.1038/308288a0 Wenzel A, Cziepluch C, Schurmann J, Schwab M: The N-myc oncoprotein is a transcriptional activator and associates with max and RB1 proteins. Prog Clin Biol Res. 1994, 385: 59-66. Weiss WA, Aldape K, Mohapatra G, Feuerstein BG, Bishop JM: Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 1997, 16: 2985-2995. 10.1093/emboj/16.11.2985 Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM: Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 1984, 224: 1121-1124. 10.1126/science.6719137 Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY, Hammond D: Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985, 313: 1111-1116. Westermann F, Muth D, Benner A, Bauer T, Henrich KO, Oberthuer A, Brors B, Beissbarth T, Vandesompele J, Pattyn F, Hero B, Konig R, Fischer M, Schwab M: Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas. Genome Biol. 2008, 9: R150- 10.1186/gb-2008-9-10-r150 White PS, Thompson PM, Gotoh T, Okawa ER, Igarashi J, Kok M, Winter C, Gregory SG, Hogarty MD, Maris JM, Brodeur GM: Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma. Oncogene. 2005, 24: 2684-2694. 10.1038/sj.onc.1208306 Bauer A, Savelyeva L, Claas A, Praml C, Berthold F, Schwab M: Smallest region of overlapping deletion in 1p36 in human neuroblastoma: a 1 Mbp cosmid and PAC contig. Genes Chromosomes Cancer. 2001, 31: 228-239. 10.1002/gcc.1139 Caron H, Spieker N, Godfried M, Veenstra M, van Sluis P, de Kraker J, Voute P, Versteeg R: Chromosome bands 1p35-36 contain two distinct neuroblastoma tumor suppressor loci, one of which is imprinted. Genes Chromosomes Cancer. 2001, 30: 168-174. 10.1002/1098-2264(200102)30:2<168::AID-GCC1072>3.0.CO;2-E Martinsson T, Sjoberg RM, Hallstensson K, Nordling M, Hedborg F, Kogner P: Delimitation of a critical tumour suppressor region at distal 1p in neuroblastoma tumours. Eur J Cancer. 1997, 33: 1997-2001. 10.1016/S0959-8049(97)00278-5 Okawa ER, Gotoh T, Manne J, Igarashi J, Fujita T, Silverman KA, Xhao H, Mosse YP, White PS, Brodeur GM: Expression and sequence analysis of candidates for the 1p36.31 tumor suppressor gene deleted in neuroblastomas. Oncogene. 2008, 27: 803-810. 10.1038/sj.onc.1210675 Schleiermacher G, Peter M, Michon J, Hugot JP, Vielh P, Zucker JM, Magdelenat H, Thomas G, Delattre O: Two distinct deleted regions on the short arm of chromosome 1 in neuroblastoma. Genes Chromosomes Cancer. 1994, 10: 275-281. 10.1002/gcc.2870100409 Takeda O, Homma C, Maseki N, Sakurai M, Kanda N, Schwab M, Nakamura Y, Kaneko Y: There may be two tumor suppressor genes on chromosome arm 1p closely associated with biologically distinct subtypes of neuroblastoma. Genes Chromosomes Cancer. 1994, 10: 30-39. 10.1002/gcc.2870100106 Thompson PM, Gotoh T, Kok M, White PS, Brodeur GM: CHD5, a new member of the chromodomain gene family, is preferentially expressed in the nervous system. Oncogene. 2003, 22: 1002-1011. 10.1038/sj.onc.1206211 Bagchi A, Papazoglu C, Wu Y, Capurso D, Brodt M, Francis D, Bredel M, Vogel H, Mills AA: CHD5 is a tumor suppressor at human 1p36. Cell. 2007, 128: 459-475. 10.1016/j.cell.2006.11.052 Fujita T, Igarashi J, Okawa ER, Gotoh T, Manne J, Kolla V, Kim J, Zhao H, Pawel BR, London WB, Maris JM, White PS, Brodeur GM: CHD5, a tumor suppressor gene deleted from 1p36.31 in neuroblastomas. J Natl Cancer Inst. 2008, 100: 940-949. 10.1093/jnci/djn176 Chen YZ, Soeda E, Yang HW, Takita J, Chai L, Horii A, Inazawa J, Ohki M, Hayashi Y: Homozygous deletion in a neuroblastoma cell line defined by a high-density STS map spanning human chromosome band 1p36. Genes Chromosomes Cancer. 2001, 31: 326-332. 10.1002/gcc.1151 Munirajan AK, Ando K, Mukai A, Takahashi M, Suenaga Y, Ohira M, Koda T, Hirota T, Ozaki T, Nakagawara A: KIF1Bbeta functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptotic cell death. J Biol Chem. 2008, 283: 24426-24434. 10.1074/jbc.M802316200 Attiyeh EF, London WB, Mosse YP, Wang Q, Winter C, Khazi D, McGrady PW, Seeger RC, Look AT, Shimada H, Brodeur GM, Cohn SL, Matthay KK, Maris JM: Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med. 2005, 353: 2243-2253. 10.1056/NEJMoa052399 Caron H, van Sluis P, de Kraker J, Bokkerink J, Egeler M, Laureys G, Slater R, Westerveld A, Voute PA, Versteeg R: Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med. 1996, 334: 225-230. 10.1056/NEJM199601253340404 Gehring M, Berthold F, Edler L, Schwab M, Amler LC: The 1p deletion is not a reliable marker for the prognosis of patients with neuroblastoma. Cancer Res. 1995, 55: 5366-5369. Meddeb M, Danglot G, Chudoba I, Venuat AM, Benard J, Avet-Loiseau H, Vasseur B, Le Paslier D, Terrier-Lacombe MJ, Hartmann O, Bernheim A: Additional copies of a 25 Mb chromosomal region originating from 17q23.1-17qter are present in 90% of high-grade neuroblastomas. Genes Chromosomes Cancer. 1996, 17: 156-165. 10.1002/(SICI)1098-2264(199611)17:3<156::AID-GCC3>3.0.CO;2-3 Van Roy N, Laureys G, Cheng NC, Willem P, Opdenakker G, Versteeg R, Speleman F: 1;17 translocations and other chromosome 17 rearrangements in human primary neuroblastoma tumors and cell lines. Genes Chromosomes Cancer. 1994, 10: 103-114. 10.1002/gcc.2870100205 Caron H, van Sluis P, van Roy N, de Kraker J, Speleman F, Voute PA, Westerveld A, Slater R, Versteeg R: Recurrent 1;17 translocations in human neuroblastoma reveal nonhomologous mitotic recombination during the S/G2 phase as a novel mechanism for loss of heterozygosity. Am J Hum Genet. 1994, 55: 341-347. Savelyeva L, Corvi R, Schwab M: Translocation involving 1p and 17q is a recurrent genetic alteration of human neuroblastoma cells. Am J Hum Genet. 1994, 55: 334-340. Laureys G, Speleman F, Opdenakker G, Benoit Y, Leroy J: Constitutional translocation t(1;17)(p36;q12-21) in a patient with neuroblastoma. Genes Chromosomes Cancer. 1990, 2: 252-254. 10.1002/gcc.2870020315 Laureys G, Speleman F, Versteeg R, Drift van der P, Chan A, Leroy J, Francke U, Opdenakker G, Van Roy N: Constitutional translocation t(1;17)(p36.31-p36.13;q11.2-q12.1) in a neuroblastoma patient. Establishment of somatic cell hybrids and identification of PND/A12M2 on chromosome 1 and NF1/SCYA7 on chromosome 17 as breakpoint flanking single copy markers. Oncogene. 1995, 10: 1087-1093. Vandepoele K, Andries V, Van Roy N, Staes K, Vandesompele J, Laureys G, De Smet E, Berx G, Speleman F, van Roy F: A constitutional translocation t(1;17)(p36.2;q11.2) in a neuroblastoma patient disrupts the human NBPF1 and ACCN1 genes. PLoS ONE. 2008, 3: e2207- 10.1371/journal.pone.0002207 Vandesompele J, Michels E, De Preter K, Menten B, Schramm A, Eggert A, Ambros PF, Combaret V, Francotte N, Antonacci F, De Paepe A, Laureys G, Speleman F, Van Roy N: Identification of 2 putative critical segments of 17q gain in neuroblastoma through integrative genomics. Int J Cancer. 2008, 122: 1177-1182. 10.1002/ijc.23156 Bown N, Cotterill S, Lastowska M, O'Neill S, Pearson AD, Plantaz D, Meddeb M, Danglot G, Brinkschmidt C, Christiansen H, Laureys G, Speleman F, Nicholson J, Bernheim A, Betts DR, Vandesompele J, Van Roy N: Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med. 1999, 340: 1954-1961. 10.1056/NEJM199906243402504 Vandesompele J, Baudis M, De Preter K, Van Roy N, Ambros P, Bown N, Brinkschmidt C, Christiansen H, Combaret V, Lastowska M, Nicholson J, O'Meara A, Plantaz D, Stallings R, Brichard B, Broecke Van den C, De Bie S, De Paepe A, Laureys G, Speleman F: Unequivocal delineation of clinicogenetic subgroups and development of a new model for improved outcome prediction in neuroblastoma. J Clin Oncol. 2005, 23: 2280-2299. 10.1200/JCO.2005.06.104 Adida C, Berrebi D, Peuchmaur M, Reyes-Mugica M, Altieri DC: Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. Lancet. 1998, 351: 882-883. 10.1016/S0140-6736(05)70294-4 Godfried MB, Veenstra M, v Sluis P, Boon K, v Asperen R, Hermus MC, v Schaik BD, Voute TP, Schwab M, Versteeg R, Caron HN: The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2. Oncogene. 2002, 21: 2097-2101. 10.1038/sj.onc.1205259 Vandesompele J, Speleman F, Van Roy N, Laureys G, Brinskchmidt C, Christiansen H, Lampert F, Lastowska M, Bown N, Pearson A, Nicholson JC, Ross F, Combaret V, Delattre O, Feuerstein BG, Plantaz D: Multicentre analysis of patterns of DNA gains and losses in 204 neuroblastoma tumors: how many genetic subgroups are there?. Med Pediatr Oncol. 2001, 36: 5-10. 10.1002/1096-911X(20010101)36:1<5::AID-MPO1003>3.0.CO;2-E McArdle L, McDermott M, Purcell R, Grehan D, O'Meara A, Breatnach F, Catchpoole D, Culhane AC, Jeffery I, Gallagher WM, Stallings RL: Oligonucleotide microarray analysis of gene expression in neuroblastoma displaying loss of chromosome 11q. Carcinogenesis. 2004, 25: 1599-1609. 10.1093/carcin/bgh173 Ando K, Ohira M, Ozaki T, Nakagawa A, Akazawa K, Suenaga Y, Nakamura Y, Koda T, Kamijo T, Murakami Y, Nakagawara A: Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation. Int J Cancer. 2008, 123: 2087-2094. 10.1002/ijc.23776 Michels E, Hoebeeck J, De Preter K, Schramm A, Brichard B, De Paepe A, Eggert A, Laureys G, Vandesompele J, Speleman F: CADM1 is a strong neuroblastoma candidate gene that maps within a 3.72 Mb critical region of loss on 11q23. BMC Cancer. 2008, 8: 173- 10.1186/1471-2407-8-173 Nowacki S, Skowron M, Oberthuer A, Fagin A, Voth H, Brors B, Westermann F, Eggert A, Hero B, Berthold F, Fischer M: Expression of the tumour suppressor gene CADM1 is associated with favourable outcome and inhibits cell survival in neuroblastoma. Oncogene. 2008, 27: 3329-3338. 10.1038/sj.onc.1210996 Breen CJ, O'Meara A, McDermott M, Mullarkey M, Stallings RL: Coordinate deletion of chromosome 3p and 11q in neuroblastoma detected by comparative genomic hybridization. Cancer Genet Cytogenet. 2000, 120: 44-49. 10.1016/S0165-4608(99)00252-6 Ejeskar K, Aburatani H, Abrahamsson J, Kogner P, Martinsson T: Loss of heterozygosity of 3p markers in neuroblastoma tumours implicate a tumour-suppressor locus distal to the FHIT gene. Br J Cancer. 1998, 77: 1787-1791. Luttikhuis ME, Powell JE, Rees SA, Genus T, Chughtai S, Ramani P, Mann JR, McConville CM: Neuroblastomas with chromosome 11q loss and single copy MYCN comprise a biologically distinct group of tumours with adverse prognosis. Br J Cancer. 2001, 85: 531-537. 10.1054/bjoc.2001.1960 Plantaz D, Vandesompele J, Van Roy N, Lastowska M, Bown N, Combaret V, Favrot MC, Delattre O, Michon J, Benard J, Hartmann O, Nicholson JC, Ross FM, Brinkschmidt C, Laureys G, Caron H, Matthay KK, Feuerstein BG, Speleman F: Comparative genomic hybridization (CGH) analysis of stage 4 neuroblastoma reveals high frequency of 11q deletion in tumors lacking MYCN amplification. Int J Cancer. 2001, 91: 680-686. 10.1002/1097-0215(200002)9999:9999<::AID-IJC1114>3.0.CO;2-R Hoebeeck J, Michels E, Menten B, Van Roy N, Eggert A, Schramm A, De Preter K, Yigit N, De Smet E, De Paepe A, Laureys G, Vandesompele J, Speleman F: High resolution tiling-path BAC array deletion mapping suggests commonly involved 3p21-p22 tumor suppressor genes in neuroblastoma and more frequent tumors. Int J Cancer. 2007, 120: 533-538. 10.1002/ijc.22326 Longo L, Panza E, Schena F, Seri M, Devoto M, Romeo G, Bini C, Pappalardo G, Tonini GP, Perri P: Genetic predisposition to familial neuroblastoma: identification of two novel genomic regions at 2p and 12p. Hum Hered. 2007, 63: 205-211. 10.1159/000099997 Shojaei-Brosseau T, Chompret A, Abel A, de Vathaire F, Raquin MA, Brugieres L, Feunteun J, Hartmann O, Bonaiti-Pellie C: Genetic epidemiology of neuroblastoma: a study of 426 cases at the Institut Gustave-Roussy in France. Pediatr Blood Cancer. 2004, 42: 99-105. 10.1002/pbc.10381 Knudson AG, Strong LC: Mutation and cancer: neuroblastoma and pheochromocytoma. Am J Hum Genet. 1972, 24: 514-532. Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual L, Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich A, Gaultier C, Lyonnet S: Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003, 33: 459-461. 10.1038/ng1130 Mosse YP, Laudenslager M, Khazi D, Carlisle AJ, Winter CL, Rappaport E, Maris JM: Germline PHOX2B mutation in hereditary neuroblastoma. Am J Hum Genet. 2004, 75: 727-730. 10.1086/424530 Trochet D, Bourdeaut F, Janoueix-Lerosey I, Deville A, de Pontual L, Schleiermacher G, Coze C, Philip N, Frebourg T, Munnich A, Lyonnet S, Delattre O, Amiel J: Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Am J Hum Genet. 2004, 74: 761-764. 10.1086/383253 Mosse YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM: Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008, 455: 930-935. 10.1038/nature07261 Caren H, Abel F, Kogner P, Martinsson T: High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours. Biochem J. 2008, 416: 153-159. 10.1042/BJ20081834 Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M, Wang L, Soda M, Kikuchi A, Igarashi T, Nakagawara A, Hayashi Y, Mano H, Ogawa S: Oncogenic mutations of ALK kinase in neuroblastoma. Nature. 2008, 455: 971-974. 10.1038/nature07399 George RE, Sanda T, Hanna M, Frohling S, Luther W 2nd, Zhang J, Ahn Y, Zhou W, London WB, McGrady P, Xue L, Zozulya S, Gregor VE, Webb TR, Gray NS, Gilliland DG, Diller L, Greulich H, Morris SW, Meyerson M, Look AT: Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature. 2008, 455: 975-978. 10.1038/nature07397 Janoueix-Lerosey I, Lequin D, Brugieres L, Ribeiro A, de Pontual L, Combaret V, Raynal V, Puisieux A, Schleiermacher G, Pierron G, Valteau-Couanet D, Frebourg T, Michon J, Lyonnet S, Amiel J, Delattre O: Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008, 455: 967-970. 10.1038/nature07398 Maris JM, Mosse YP, Bradfield JP, Hou C, Monni S, Scott RH, Asgharzadeh S, Attiyeh EF, Diskin SJ, Laudenslager M, Winter C, Cole KA, Glessner JT, Kim C, Frackelton EC, Casalunovo T, Eckert AW, Capasso M, Rappaport EF, McConville C, London WB, Seeger RC, Rahman N, Devoto M, Grant SF, Li H, Hakonarson H: Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med. 2008, 358: 2585-2593. 10.1056/NEJMoa0708698 Capasso M, Devoto M, Hou C, Asgharzadeh S, Glessner JT, Attiyeh EF, Mosse YP, Kim C, Diskin SJ, Cole KA, Bosse K, Diamond M, Laudenslager M, Winter C, Bradfield JP, Scott RH, Jagannathan J, Garris M, McConville C, London WB, Seeger RC, Grant SF, Li H, Rahman N, Rappaport E, Hakonarson H, Maris JM: Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nat Genet. 2009, 41: 718-723. 10.1038/ng.374 Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL, Yang MC, Hwang LY, Bowcock AM, Baer R: Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet. 1996, 14: 430-440. 10.1038/ng1296-430 Kallioniemi OP, Kallioniemi A, Piper J, Isola J, Waldman FM, Gray JW, Pinkel D: Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer. 1994, 10: 231-243. 10.1002/gcc.2870100403 Michels E, Vandesompele J, De Preter K, Hoebeeck J, Vermeulen J, Schramm A, Molenaar JJ, Menten B, Marques B, Stallings RL, Combaret V, Devalck C, De Paepe A, Versteeg R, Eggert A, Laureys G, Van Roy N, Speleman F: ArrayCGH-based classification of neuroblastoma into genomic subgroups. Genes Chromosomes Cancer. 2007, 46: 1098-1108. 10.1002/gcc.20496 Janoueix-Lerosey I, Schleiermacher G, Michels E, Mosseri V, Ribeiro A, Lequin D, Vermeulen J, Couturier J, Peuchmaur M, Valent A, Plantaz D, Rubie H, Valteau-Couanet D, Thomas C, Combaret V, Rousseau R, Eggert A, Michon J, Speleman F, Delattre O: Overall genomic pattern is a predictor of outcome in neuroblastoma. J Clin Oncol. 2009, 27: 1026-1033. 10.1200/JCO.2008.16.0630 Mosse YP, Diskin SJ, Wasserman N, Rinaldi K, Attiyeh EF, Cole K, Jagannathan J, Bhambhani K, Winter C, Maris JM: Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression. Genes Chromosomes Cancer. 2007, 46: 936-949. 10.1002/gcc.20477 Vandesompele J, Van Roy N, Van Gele M, Laureys G, Ambros P, Heimann P, Devalck C, Schuuring E, Brock P, Otten J, Gyselinck J, De Paepe A, Speleman F: Genetic heterogeneity of neuroblastoma studied by comparative genomic hybridization. Genes Chromosomes Cancer. 1998, 23: 141-152. 10.1002/(SICI)1098-2264(199810)23:2<141::AID-GCC7>3.0.CO;2-2 Michels E, De Preter K, Van Roy N, Speleman F: Detection of DNA copy number alterations in cancer by array comparative genomic hybridization. Genet Med. 2007, 9: 574-584. Tomioka N, Oba S, Ohira M, Misra A, Fridlyand J, Ishii S, Nakamura Y, Isogai E, Hirata T, Yoshida Y, Todo S, Kaneko Y, Albertson DG, Pinkel D, Feuerstein BG, Nakagawara A: Novel risk stratification of patients with neuroblastoma by genomic signature, which is independent of molecular signature. Oncogene. 2008, 27: 441-449. 10.1038/sj.onc.1210661 Asgharzadeh S, Pique-Regi R, Sposto R, Wang H, Yang Y, Shimada H, Matthay K, Buckley J, Ortega A, Seeger RC: Prognostic significance of gene expression profiles of metastatic neuroblastomas lacking MYCN gene amplification. J Natl Cancer Inst. 2006, 98: 1193-1203. Oberthuer A, Berthold F, Warnat P, Hero B, Kahlert Y, Spitz R, Ernestus K, Konig R, Haas S, Eils R, Schwab M, Brors B, Westermann F, Fischer M: Customized oligonucleotide microarray gene expression-based classification of neuroblastoma patients outperforms current clinical risk stratification. J Clin Oncol. 2006, 24: 5070-5078. 10.1200/JCO.2006.06.1879 Ohira M, Oba S, Nakamura Y, Isogai E, Kaneko S, Nakagawa A, Hirata T, Kubo H, Goto T, Yamada S, Yoshida Y, Fuchioka M, Ishii S, Nakagawara A: Expression profiling using a tumor-specific cDNA microarray predicts the prognosis of intermediate risk neuroblastomas. Cancer Cell. 2005, 7: 337-350. 10.1016/j.ccr.2005.03.019 Schramm A, Schulte JH, Klein-Hitpass L, Havers W, Sieverts H, Berwanger B, Christiansen H, Warnat P, Brors B, Eils J, Eils R, Eggert A: Prediction of clinical outcome and biological characterization of neuroblastoma by expression profiling. Oncogene. 2005, 24: 7902-7912. 10.1038/sj.onc.1208936 Wei JS, Greer BT, Westermann F, Steinberg SM, Son CG, Chen QR, Whiteford CC, Bilke S, Krasnoselsky AL, Cenacchi N, Catchpoole D, Berthold F, Schwab M, Khan J: Prediction of clinical outcome using gene expression profiling and artificial neural networks for patients with neuroblastoma. Cancer Res. 2004, 64: 6883-6891. 10.1158/0008-5472.CAN-04-0695 Berwanger B, Hartmann O, Bergmann E, Bernard S, Nielsen D, Krause M, Kartal A, Flynn D, Wiedemeyer R, Schwab M, Schafer H, Christiansen H, Eilers M: Loss of a FYN-regulated differentiation and growth arrest pathway in advanced stage neuroblastoma. Cancer Cell. 2002, 2: 377-386. 10.1016/S1535-6108(02)00179-4 Vermeulen J, De Preter K, Naranjo A, Vercruysse L, Van Roy N, Hellemans J, Swerts K, Bravo S, Scaruffi P, Tonini GP, De Bernardi B, Noguera R, Piqueras M, Canete A, Castel V, Janoueix-Lerosey I, Delattre O, Schleiermacher G, Michon J, Combaret V, Fischer M, Oberthuer A, Ambros PF, Beiske K, Benard J, Marques B, Rubie H, Kohler J, Potschger U, Ladenstein R, et al.: Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study. Lancet Oncol. 2009, 10: 663-671. 10.1016/S1470-2045(09)70154-8 De Preter K, Vandesompele J, Heimann P, Yigit N, Beckman S, Schramm A, Eggert A, Stallings RL, Benoit Y, Renard M, De Paepe A, Laureys G, Pahlman S, Speleman F: Human fetal neuroblast and neuroblastoma transcriptome analysis confirms neuroblast origin and highlights neuroblastoma candidate genes. Genome Biol. 2006, 7: R84- 10.1186/gb-2006-7-9-r84 Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, Reich M, Hieronymus H, Wei G, Armstrong SA, Haggarty SJ, Clemons PA, Wei R, Carr SA, Lander ES, Golub TR: The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006, 313: 1929-1935. 10.1126/science.1132939 De Preter K, De Brouwer S, Van Maerken T, Pattyn F, Schramm A, Eggert A, Vandesompele J, Speleman F: Meta-mining of neuroblastoma and neuroblast gene expression profiles reveals candidate therapeutic compounds. Clin Cancer Res. 2009, 15: 3690-3696. 10.1158/1078-0432.CCR-08-2699 Ongenaert M, Van Neste L, De Meyer T, Menschaert G, Bekaert S, Van Criekinge W: PubMeth: a cancer methylation database combining text-mining and expert annotation. Nucleic Acids Res. 2008, 36: D842-D846. 10.1093/nar/gkm788 Abe M, Ohira M, Kaneda A, Yagi Y, Yamamoto S, Kitano Y, Takato T, Nakagawara A, Ushijima T: CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas. Cancer Res. 2005, 65: 828-834. Alaminos M, Davalos V, Cheung NK, Gerald WL, Esteller M: Clustering of gene hypermethylation associated with clinical risk groups in neuroblastoma. J Natl Cancer Inst. 2004, 96: 1208-1219. Banelli B, Gelvi I, Di Vinci A, Scaruffi P, Casciano I, Allemanni G, Bonassi S, Tonini GP, Romani M: Distinct CpG methylation profiles characterize different clinical groups of neuroblastic tumors. Oncogene. 2005, 24: 5619-5628. 10.1038/sj.onc.1208722 Hoebeeck J, Michels E, Pattyn F, Combaret V, Vermeulen J, Yigit N, Hoyoux C, Laureys G, De Paepe A, Speleman F, Vandesompele J: Aberrant methylation of candidate tumor suppressor genes in neuroblastoma. Cancer Lett. 2009, 273: 336-346. 10.1016/j.canlet.2008.08.019 Yang Q, Kiernan CM, Tian Y, Salwen HR, Chlenski A, Brumback BA, London WB, Cohn SL: Methylation of CASP8, DCR2, and HIN-1 in neuroblastoma is associated with poor outcome. Clin Cancer Res. 2007, 13: 3191-3197. 10.1158/1078-0432.CCR-06-2846 Misawa A, Tanaka S, Yagyu S, Tsuchiya K, Iehara T, Sugimoto T, Hosoi H: RASSF1A hypermethylation in pretreatment serum DNA of neuroblastoma patients: a prognostic marker. Br J Cancer. 2009, 100: 399-404. 10.1038/sj.bjc.6604887 Yagyu S, Gotoh T, Iehara T, Miyachi M, Katsumi Y, Tsubai-Shimizu S, Kikuchi K, Tamura S, Tsuchiya K, Imamura T, Misawa-Furihata A, Sugimoto T, Sawada T, Hosoi H: Circulating methylated-DCR2 gene in serum as an indicator of prognosis and therapeutic efficacy in patients with MYCN nonamplified neuroblastoma. Clin Cancer Res. 2008, 14: 7011-7019. 10.1158/1078-0432.CCR-08-1249 Esquela-Kerscher A, Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006, 6: 259-269. 10.1038/nrc1840 Chen Y, Stallings RL: Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis, differentiation, and apoptosis. Cancer Res. 2007, 67: 976-983. 10.1158/0008-5472.CAN-06-3667 Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR: MicroRNA expression profiles classify human cancers. Nature. 2005, 435: 834-838. 10.1038/nature03702 Schulte JH, Horn S, Otto T, Samans B, Heukamp LC, Eilers UC, Krause M, Astrahantseff K, Klein-Hitpass L, Buettner R, Schramm A, Christiansen H, Eilers M, Eggert A, Berwanger B: MYCN regulates oncogenic microRNAs in neuroblastoma. Int J Cancer. 2008, 122: 699-704. 10.1002/ijc.23153 Otto T, Horn S, Brockmann M, Eilers U, Schuttrumpf L, Popov N, Kenney AM, Schulte JH, Beijersbergen R, Christiansen H, Berwanger B, Eilers M: Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell. 2009, 15: 67-78. 10.1016/j.ccr.2008.12.005 Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, Yatabe Y, Kawahara K, Sekido Y, Takahashi T: A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005, 65: 9628-9632. 10.1158/0008-5472.CAN-05-2352 O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT: c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005, 435: 839-843. 10.1038/nature03677 Uziel T, Karginov FV, Xie S, Parker JS, Wang YD, Gajjar A, He L, Ellison D, Gilbertson RJ, Hannon G, Roussel MF: The miR-17~92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma. Proc Natl Acad Sci USA. 2009, 106: 2812-2817. 10.1073/pnas.0809579106 Fontana L, Fiori ME, Albini S, Cifaldi L, Giovinazzi S, Forloni M, Boldrini R, Donfrancesco A, Federici V, Giacomini P, Peschle C, Fruci D: Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. PLoS ONE. 2008, 3: e2236- 10.1371/journal.pone.0002236 Wei JS, Song YK, Durinck S, Chen QR, Cheuk AT, Tsang P, Zhang Q, Thiele CJ, Slack A, Shohet J, Khan J: The MYCN oncogene is a direct target of miR-34a. Oncogene. 2008, 27: 5204-5213. 10.1038/onc.2008.154 Bilke S, Chen QR, Wei JS, Khan J: Whole chromosome alterations predict survival in high-risk neuroblastoma without MYCN amplification. Clin Cancer Res. 2008, 14: 5540-5547. 10.1158/1078-0432.CCR-07-4461 Welch C, Chen Y, Stallings RL: MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene. 2007, 26: 5017-5022. 10.1038/sj.onc.1210293 Maris JM, Hogarty MD, Bagatell R, Cohn SL: Neuroblastoma. Lancet. 2007, 369: 2106-2120. 10.1016/S0140-6736(07)60983-0 Wagner LM, Danks MK: New therapeutic targets for the treatment of high-risk neuroblastoma. J Cell Biochem. 2009, 107: 46-57. 10.1002/jcb.22094 Darnell JE: Transcription factors as targets for cancer therapy. Nat Rev Cancer. 2002, 2: 740-749. 10.1038/nrc906 Lu X, Pearson A, Lunec J: The MYCN oncoprotein as a drug development target. Cancer Lett. 2003, 197: 125-130. 10.1016/S0304-3835(03)00096-X Mo H, Henriksson M: Identification of small molecules that induce apoptosis in a Myc-dependent manner and inhibit Myc-driven transformation. Proc Natl Acad Sci USA. 2006, 103: 6344-6349. 10.1073/pnas.0601418103 Mo H, Vita M, Crespin M, Henriksson M: Myc overexpression enhances apoptosis induced by small molecules. Cell Cycle. 2006, 5: 2191-2194. Burkhart CA, Cheng AJ, Madafiglio J, Kavallaris M, Mili M, Marshall GM, Weiss WA, Khachigian LM, Norris MD, Haber M: Effects of MYCN antisense oligonucleotide administration on tumorigenesis in a murine model of neuroblastoma. J Natl Cancer Inst. 2003, 95: 1394-1403. Negroni A, Scarpa S, Romeo A, Ferrari S, Modesti A, Raschella G: Decrease of proliferation rate and induction of differentiation by a MYCN antisense DNA oligomer in a human neuroblastoma cell line. Cell Growth Differ. 1991, 2: 511-518. Kang JH, Rychahou PG, Ishola TA, Qiao J, Evers BM, Chung DH: MYCN silencing induces differentiation and apoptosis in human neuroblastoma cells. Biochem Biophys Res Commun. 2006, 351: 192-197. 10.1016/j.bbrc.2006.10.020 Nara K, Kusafuka T, Yoneda A, Oue T, Sangkhathat S, Fukuzawa M: Silencing of MYCN by RNA interference induces growth inhibition, apoptotic activity and cell differentiation in a neuroblastoma cell line with MYCN amplification. Int J Oncol. 2007, 30: 1189-1196. Caren H, Erichsen J, Olsson L, Enerback C, Sjoberg RM, Abrahamsson J, Kogner P, Martinsson T: High-resolution array copy number analyses for detection of deletion, gain, amplification and copy-neutral LOH in primary neuroblastoma tumors: four cases of homozygous deletions of the CDKN2A gene. BMC Genomics. 2008, 9: 353- 10.1186/1471-2164-9-353 Carr J, Bell E, Pearson AD, Kees UR, Beris H, Lunec J, Tweddle DA: Increased frequency of aberrations in the p53/MDM2/p14(ARF) pathway in neuroblastoma cell lines established at relapse. Cancer Res. 2006, 66: 2138-2145. 10.1158/0008-5472.CAN-05-2623 Cattelani S, Defferrari R, Marsilio S, Bussolari R, Candini O, Corradini F, Ferrari-Amorotti G, Guerzoni C, Pecorari L, Menin C, Bertorelle R, Altavista P, McDowell HP, Boldrini R, Dominici C, Tonini GP, Raschella G, Calabretta B: Impact of a single nucleotide polymorphism in the MDM2 gene on neuroblastoma development and aggressiveness: results of a pilot study on 239 patients. Clin Cancer Res. 2008, 14: 3248-3253. 10.1158/1078-0432.CCR-07-4725 Cui H, Hu B, Li T, Ma J, Alam G, Gunning WT, Ding HF: Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. Am J Pathol. 2007, 170: 1370-1378. 10.2353/ajpath.2007.060754 Perfumo C, Parodi S, Mazzocco K, Defferrari R, Inga A, Haupt R, Fronza G, Tonini GP: Impact of MDM2 SNP309 genotype on progression and survival of stage 4 neuroblastoma. Eur J Cancer. 2008, 44: 2634-2639. 10.1016/j.ejca.2008.08.018 Slack A, Chen Z, Tonelli R, Pule M, Hunt L, Pession A, Shohet JM: The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. Proc Natl Acad Sci USA. 2005, 102: 731-736. 10.1073/pnas.0405495102 Thompson PM, Maris JM, Hogarty MD, Seeger RC, Reynolds CP, Brodeur GM, White PS: Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma. Cancer Res. 2001, 61: 679-686. Valsesia-Wittmann S, Magdeleine M, Dupasquier S, Garin E, Jallas AC, Combaret V, Krause A, Leissner P, Puisieux A: Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell. 2004, 6: 625-630. 10.1016/j.ccr.2004.09.033 Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA: In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004, 303: 844-848. 10.1126/science.1092472 Van Maerken T, Speleman F, Vermeulen J, Lambertz I, De Clercq S, De Smet E, Yigit N, Coppens V, Philippe J, De Paepe A, Marine JC, Vandesompele J: Small-molecule MDM2 antagonists as a new therapy concept for neuroblastoma. Cancer Res. 2006, 66: 9646-9655. 10.1158/0008-5472.CAN-06-0792 Barbieri E, Mehta P, Chen Z, Zhang L, Slack A, Berg S, Shohet JM: MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death. Mol Cancer Ther. 2006, 5: 2358-2365. 10.1158/1535-7163.MCT-06-0305 Michaelis M, Rothweiler F, Klassert D, von Deimling A, Weber K, Fehse B, Kammerer B, Doerr HW, Cinatl J: Reversal of P-glycoprotein-mediated multidrug resistance by the murine double minute 2 antagonist nutlin-3. Cancer Res. 2009, 69: 416-421. 10.1158/0008-5472.CAN-08-1856 Osajima-Hakomori Y, Miyake I, Ohira M, Nakagawara A, Nakagawa A, Sakai R: Biological role of anaplastic lymphoma kinase in neuroblastoma. Am J Pathol. 2005, 167 (1-7-X): 213-222. Zhang J, Yang PL, Gray NS: Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009, 9: 28-39. 10.1038/nrc2559 McDermott U, Iafrate AJ, Gray NS, Shioda T, Classon M, Maheswaran S, Zhou W, Choi HG, Smith SL, Dowell L, Ulkus LE, Kuhlmann G, Greninger P, Christensen JG, Haber DA, Settleman J: Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res. 2008, 68: 3389-3395. 10.1158/0008-5472.CAN-07-6186 Li R, Morris SW: Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapy. Med Res Rev. 2008, 28: 372-412. 10.1002/med.20109