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Molecular Genetics of Neuroblastoma

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Diagnostic and Therapeutic Nuclear Medicine for Neuroendocrine Tumors

Part of the book series: Contemporary Endocrinology ((COE))

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Abstract

Neuroblastoma is the most common extracranial solid tumor of childhood derived from primitive neural crest cells of the sympathetic nervous system. Recent next-generation sequencing and genome-wide association studies of tumor samples from neuroblastoma patients have discovered new germline mutations, multiple somatically acquired genetic alterations, and single nucleotide polymorphisms in the past decade, which have led to a more comprehensive understanding of the underlying genetic events that predispose to the development of neuroblastoma. To understand the genetic underpinnings of neuroblastoma, this chapter will review the molecular genetics of this pediatric tumor, emphasizing the most recent discoveries concerning genetic mutations, epigenetic alterations, and single nucleotide polymorphisms that are associated with neuroblastoma predisposition and pathogenesis, and how this information is leading to novel approaches to targeted therapy.

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Abbreviations

131I-MIBG:

131I-metaiodobenzylguanidine

AKT:

V-Akt murine thymoma viral oncogene homolog

ALCL:

Anaplastic large cell lymphomas

ALK:

Anaplastic lymphoma kinase

ALT:

Alternative lengthening of telomeres

ARID1A:

AT-rich interactive domain 1A (SWI-like)

ARID1B:

AT-rich interactive domain 1B (SWI-like)

ATM:

Ataxia telangiectasia mutated

ATRA:

All-trans retinoic acid

ATRX:

Alpha thalassemia/mental retardation syndrome X-linked

BARD1:

BRCA1-associated RING domain 1

BARD1ß:

BRCA1-associated RING domain 1, beta isoform

BCL2:

B-cell CLL/lymphoma 2

BDNF:

Brain-derived neurotrophic factor

BIM:

BCL2-like 11

BMI1:

B lymphoma Mo-MLV insertion region 1 homolog

BRAF:

B-Raf proto-oncogene, serine/threonine kinase

CADM1:

Cell adhesion molecule 1

CAMTA1:

Calmodulin-binding transcription activator 1

CASC15:

Cancer susceptibility candidate 15

CASC15-S:

CASC15 short isoform

CASP8 Caspase 8:

Apoptosis-related cysteine peptidase

CASZ1:

Castor zinc finger 1

CCHS:

Congenital central hypoventilation syndrome

CCND1:

Cyclin D1

CDK:

Cyclin-dependent kinase

CDK4:

Cyclin-dependent kinase 4

CDK6:

Cyclin-dependent kinase 6

CDKN1A:

Cyclin-dependent kinase inhibitor 1A (P21, Cip1)

CDKN2A:

Cyclin-dependent kinase inhibitor 2A

CHD5:

Chromodomain helicase DNA-binding protein 5

CHK1:

Checkpoint kinase 1

CLU:

Clusterin

CRKL:

V-Crk avian sarcoma virus CT10 oncogene homolog-like

CSC:

Cancer stem cell

CSF3R:

Colony-stimulating factor 3 receptor (granulocyte)

DKK1:

Dickkopf WNT signaling pathway inhibitor 1

DOCK8:

Dedicator of cytokinesis 8

E2F3:

E2F transcription factor 3

EFS:

Event-free survival

EZH2:

Enhancer of zeste 2 polycomb repressive complex 2 subunit

FACT:

Facilitates chromatin transcription

FAN1:

FANCD2/FANCI-associated nuclease 1 2 3 4

FANCM:

Fanconi anemia, complementation group M

FGFR1:

Fibroblast growth factor receptor 1

G-CSF:

Colony-stimulating factor

GATA:

GATA-binding protein

GATA3:

GATA-binding protein 3

GD2:

Surface glycolipid molecule disialoganglioside

GWAS:

Genome-wide association study

HDACs:

Histone deacetylases

HRAS:

Harvey rat sarcoma viral oncogene homolog

HSCR:

Hirschsprung disease

INRGSS:

International Neuroblastoma Risk Group Staging System

INSS:

International Neuroblastoma Staging System

JAK:

Janus kinase

KIF1B-beta:

Kinesin family member 1B, beta isoform

KRAS:

Kirsten RAS viral oncogene homolog

LIN28B:

Lin-28 homolog B

LMO1:

LIM domain only 1

lncRNA:

Long noncoding RNA

LSD1:

Lysine-specific demethylase

MAPK:

Mitogen-activated protein kinase

MAX:

MYC Associated factor X

miRNA:

microRNA

MIZ1:

Zinc finger and BTB domain containing 17

mTOR:

Mechanistic target of rapamycin (serine/threonine kinase)

MYCN:

V-Myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog

NBAT-1:

Neuroblastoma-associated transcript 1

NET:

Norepinephrine transporter

NF1:

Neurofibromin 1

NGFR:

Nerve growth factor receptor

NPM1:

Nucleophosmin

NRAS:

Neuroblastoma RAS viral (V-Ras) oncogene homolog

NuRD:

Nuclear remodeling and histone deacetylase

ODC1:

Ornithine decarboxylase 1

OS:

Overall survival

PCC/PGL:

Pheochromocytomas and paragangliomas

PHOX2B:

Paired-like homeobox 2B

PI3K:

Phosphatidylinositol-4,5-bisphosphate 3-kinase

pRb:

Retinoblastoma 1

PRC1:

Polycomb repressive complex 1

PRC2:

Polycomb repressive complex 2

PTPN11:

Protein tyrosine phosphatase, non-receptor type 11

PTPN14:

Protein tyrosine phosphatase, non-receptor type 14

PTPRD:

Protein tyrosine phosphatase, receptor type D

RAP1:

Ras-related Protein 1

RASSF1A:

Ras association (RalGDS/AF-6) domain family member 1

ROS1:

ROS proto-oncogene 1, receptor tyrosine kinase

SDHB:

Succinate dehydrogenase complex, subunit B

SHH:

Sonic hedgehog

SNP:

Single nucleotide polymorphism

SP1:

Specificity protein 1

STAT:

Signal transducer and activator of transcription

STAT3:

Signal transducer and activator of transcription 3

SWI/SNF:

SWItch/Sucrose Non-fermentable, a nucleosome-remodeling complex

T-UCRs:

Transcribed ultra-conserved regions

TERT:

Telomerase reverse transcriptase

TGF-beta:

Transforming growth factor, beta 1

TIAM1:

T-cell lymphoma invasion and metastasis 1

TP53:

Tumor protein P53

TSLC1:

Tumor suppressor in lung cancer 1

WGS:

Whole-genome sequencing

XLMR:

X-linked mental retardation

References

  1. Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007;369(9579):2106–20.

    Article  CAS  PubMed  Google Scholar 

  3. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003;3(3):203–16.

    Article  CAS  PubMed  Google Scholar 

  4. Bosse KR, Maris JM. Advances in the translational genomics of neuroblastoma: from improving risk stratification and revealing novel biology to identifying actionable genomic alterations. Cancer. 2015;122:20–33.

    Article  PubMed  CAS  Google Scholar 

  5. Schulte JH, Eggert A. Neuroblastoma. Crit Rev Oncog. 2015;20(3–4):245–70.

    Article  PubMed  Google Scholar 

  6. Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, Gerbing RB, London WB, Villablanca JG. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study. J Clin Oncol. 2009;27(7):1007–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Canete A, Gerrard M, Rubie H, Castel V, Di Cataldo A, Munzer C, Ladenstein R, Brichard B, Bermudez JD, Couturier J, de Bernardi B, Pearson AJ, Michon J. Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol. 2009;27(7):1014–9.

    Article  PubMed  Google Scholar 

  8. Tonini GP, Longo L, Coco S, Perri P. Familial neuroblastoma: a complex heritable disease. Cancer Lett. 2003;197(1-2):41–5.

    Article  CAS  PubMed  Google Scholar 

  9. Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, Carter SL, Cibulskis K, Hanna M, Kiezun A, Kim J, Lawrence MS, Lichenstein L, McKenna A, Pedamallu CS, Ramos AH, et al. The genetic landscape of high-risk neuroblastoma. Nat Genet. 2013;45(3):279–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sausen M, Leary RJ, Jones S, Wu J, Reynolds CP, Liu X, Blackford A, Parmigiani G, Diaz Jr LA, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE, Hogarty MD. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet. 2013;45(1):12–7.

    Article  CAS  PubMed  Google Scholar 

  11. Cheung NK, Zhang J, Lu C, Parker M, Bahrami A, Tickoo SK, Heguy A, Pappo AS, Federico S, Dalton J, Cheung IY, Ding L, Fulton R, Wang J, Chen X, Becksfort J, et al. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA. 2012;307(10):1062–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, Hamdi M, van Nes J, Westerman BA, van Arkel J, Ebus ME, Haneveld F, Lakeman A, Schild L, Molenaar P, Stroeken P, et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature. 2012;483(7391):589–93.

    Article  CAS  PubMed  Google Scholar 

  13. Lee YH, Kim JH, Song GG. Genome-wide pathway analysis in neuroblastoma. Tumour Biol. 2014;35(4):3471–85.

    Article  CAS  PubMed  Google Scholar 

  14. Capasso M, Diskin SJ. Genetics and genomics of neuroblastoma. Cancer Treat Res. 2010;155:65–84.

    Article  CAS  PubMed  Google Scholar 

  15. le Nguyen B, Diskin SJ, Capasso M, Wang K, Diamond MA, Glessner J, Kim C, Attiyeh EF, Mosse YP, Cole K, Iolascon A, Devoto M, Hakonarson H, Li HK, Maris JM. Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility Loci. PLoS Genet. 2011;7(3):e1002026.

    Article  CAS  PubMed Central  Google Scholar 

  16. 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, et al. Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nat Genet. 2009;41(6):718–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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, Force IT. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;27(2):289–97.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 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, et al. Overall genomic pattern is a predictor of outcome in neuroblastoma. J Clin Oncol. 2009;27(7):1026–33.

    Article  PubMed  Google Scholar 

  19. 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(4653):1121–4.

    Article  CAS  PubMed  Google Scholar 

  20. 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(18):1111–6.

    Article  CAS  PubMed  Google Scholar 

  21. Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, Haas-Kogan DA, Laquaglia MP, Yu AL, Diller L, Buxton A, Park JR, Cohn SL, Maris JM, Reynolds CP, Villablanca JG. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013;14(10):999–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schneider SS, Hiemstra JL, Zehnbauer BA, Taillon-Miller P, Le Paslier DL, Vogelstein B, Brodeur GM. Isolation and structural analysis of a 1.2-megabase N-myc amplicon from a human neuroblastoma. Mol Cell Biol. 1992;12(12):5563–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Reiter JL, Brodeur GM. High-resolution mapping of a 130-kb core region of the MYCN amplicon in neuroblastomas. Genomics. 1996;32(1):97–103.

    Article  CAS  PubMed  Google Scholar 

  24. Chan HS, Gallie BL, DeBoer G, Haddad G, Ikegaki N, Dimitroulakos J, Yeger H, Ling V. MYCN protein expression as a predictor of neuroblastoma prognosis. Clin Cancer Res. 1997;3(10):1699–706.

    CAS  PubMed  Google Scholar 

  25. Bordow SB, Norris MD, Haber PS, Marshall GM, Haber M. Prognostic significance of MYCN oncogene expression in childhood neuroblastoma. J Clin Oncol. 1998;16(10):3286–94.

    CAS  PubMed  Google Scholar 

  26. Cohn SL, London WB, Huang D, Katzenstein HM, Salwen HR, Reinhart T, Madafiglio J, Marshall GM, Norris MD, Haber M. MYCN expression is not prognostic of adverse outcome in advanced-stage neuroblastoma with nonamplified MYCN. J Clin Oncol. 2000;18(21):3604–13.

    CAS  PubMed  Google Scholar 

  27. Alaminos M, Gerald WL, Cheung NK. Prognostic value of MYCN and ID2 overexpression in neuroblastoma. Pediatr Blood Cancer. 2005;45(7):909–15.

    Article  PubMed  Google Scholar 

  28. Valentijn LJ, Koster J, Haneveld F, Aissa RA, van Sluis P, Broekmans ME, Molenaar JJ, van Nes J, Versteeg R. Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification. Proc Natl Acad Sci U S A. 2012;109(47):19190–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Weiss WA, Aldape K, Mohapatra G, Feuerstein BG, Bishop JM. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 1997;16(11):2985–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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(5):1189–96.

    CAS  PubMed  Google Scholar 

  31. Woo CW, Tan F, Cassano H, Lee J, Lee KC, Thiele CJ. Use of RNA interference to elucidate the effect of MYCN on cell cycle in neuroblastoma. Pediatr Blood Cancer. 2008;50(2):208–12.

    Article  PubMed  Google Scholar 

  32. Ochiai H, Takenobu H, Nakagawa A, Yamaguchi Y, Kimura M, Ohira M, Okimoto Y, Fujimura Y, Koseki H, Kohno Y, Nakagawara A, Kamijo T. Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bbeta and TSLC1 in neuroblastoma. Oncogene. 2010;29(18):2681–90.

    Article  CAS  PubMed  Google Scholar 

  33. Huang R, Cheung NK, Vider J, Cheung IY, Gerald WL, Tickoo SK, Holland EC, Blasberg RG. MYCN and MYC regulate tumor proliferation and tumorigenesis directly through BMI1 in human neuroblastomas. FASEB J. 2011;25(12):4138–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hasan MK, Nafady A, Takatori A, Kishida S, Ohira M, Suenaga Y, Hossain S, Akter J, Ogura A, Nakamura Y, Kadomatsu K, Nakagawara A. ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma. Sci Rep. 2013;3:3450.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Chen L, Iraci N, Gherardi S, Gamble LD, Wood KM, Perini G, Lunec J, Tweddle DA. p53 is a direct transcriptional target of MYCN in neuroblastoma. Cancer Res. 2010;70(4):1377–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Carter DR, Murray J, Cheung BB, Gamble L, Koach J, Tsang J, Sutton S, Kalla H, Syed S, Gifford AJ, Issaeva N, Biktasova A, Atmadibrata B, Sun Y, Sokolowski N, Ling D. Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma. Sci Transl Med. 2015;7(312):312ra176.

    Article  PubMed  CAS  Google Scholar 

  37. Hogarty MD, Norris MD, Davis K, Liu X, Evageliou NF, Hayes CS, Pawel B, Guo R, Zhao H, Sekyere E, Keating J, Thomas W, Cheng NC, Murray J, Smith J, Sutton R, et al. ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma. Cancer Res. 2008;68(23):9735–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Iraci N, Diolaiti D, Papa A, Porro A, Valli E, Gherardi S, Herold S, Eilers M, Bernardoni R, Della Valle G, Perini G. A SP1/MIZ1/MYCN repression complex recruits HDAC1 at the TRKA and p75NTR promoters and affects neuroblastoma malignancy by inhibiting the cell response to NGF. Cancer Res. 2011;71(2):404–12.

    Article  CAS  PubMed  Google Scholar 

  39. Wenzel A, Schwab M. The mycN/max protein complex in neuroblastoma. Short review. Eur J Cancer. 1995;31A(4):516–9.

    Article  CAS  PubMed  Google Scholar 

  40. Corvetta D, Chayka O, Gherardi S, D’Acunto CW, Cantilena S, Valli E, Piotrowska I, Perini G, Sala A. Physical interaction between MYCN oncogene and polycomb repressive complex 2 (PRC2) in neuroblastoma: functional and therapeutic implications. J Biol Chem. 2013;288(12):8332–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. He S, Liu Z, Oh DY, Thiele CJ. MYCN and the epigenome. Front Oncol. 2013;3:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, Wang R, Green DR, Tessarollo L, Casellas R, Zhao K, Levens D. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell. 2012;151(1):68–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE, Lee TI, Young RA. Transcriptional amplification in tumor cells with elevated c-Myc. Cell. 2012;151(1):56–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Peifer M, Hertwig F, Roels F, Dreidax D, Gartlgruber M, Menon R, Kramer A, Roncaioli JL, Sand F, Heuckmann JM, Ikram F, Schmidt R, Ackermann S, Engesser A, Kahlert Y, Vogel W, et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature. 2015;526(7575):700–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Valentijn LJ, Koster J, Zwijnenburg DA, Hasselt NE, van Sluis P, Volckmann R, van Noesel MM, George RE, Tytgat GA, Molenaar JJ, Versteeg R. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat Genet. 2015;47(12):1411–4.

    Article  CAS  PubMed  Google Scholar 

  46. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339(6122):957–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Davis CF, Ricketts CJ, Wang M, Yang L, Cherniack AD, Shen H, Buhay C, Kang H, Kim SC, Fahey CC, Hacker KE, Bhanot G, Gordenin DA, Chu A, Gunaratne PH, Biehl M, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell. 2014;26(3):319–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mac SM, D’Cunha CA, Farnham PJ. Direct recruitment of N-myc to target gene promoters. Mol Carcinog. 2000;29(2):76–86.

    Article  CAS  PubMed  Google Scholar 

  49. Mosse YP, Greshock J, Weber BL, Maris JM. Measurement and relevance of neuroblastoma DNA copy number changes in the post-genome era. Cancer Lett. 2005;228(1-2):83–90.

    Article  CAS  PubMed  Google Scholar 

  50. 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(10):936–49.

    Article  CAS  PubMed  Google Scholar 

  51. Chen QR, Bilke S, Wei JS, Whiteford CC, Cenacchi N, Krasnoselsky AL, Greer BT, Son CG, Westermann F, Berthold F, Schwab M, Catchpoole D, Khan J. cDNA array-CGH profiling identifies genomic alterations specific to stage and MYCN-amplification in neuroblastoma. BMC Genomics. 2004;5:70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. 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(1):5–10.

    Article  CAS  PubMed  Google Scholar 

  53. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. van Noesel MM, Versteeg R. Pediatric neuroblastomas: genetic and epigenetic ‘danse macabre’. Gene. 2004;325:1–15.

    Article  PubMed  CAS  Google Scholar 

  55. 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, Children’s OG. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med. 2005;353(21):2243–53.

    Article  CAS  PubMed  Google Scholar 

  56. Bader SA, Fasching C, Brodeur GM, Stanbridge EJ. Dissociation of suppression of tumorigenicity and differentiation in vitro effected by transfer of single human chromosomes into human neuroblastoma cells. Cell Growth Differ. 1991;2(5):245–55.

    CAS  PubMed  Google Scholar 

  57. Henrich KO, Schwab M, Westermann F. 1p36 tumor suppression--a matter of dosage? Cancer Res. 2012;72(23):6079–88.

    Article  CAS  PubMed  Google Scholar 

  58. Kolla V, Naraparaju K, Zhuang T, Higashi M, Kolla S, Blobel GA, Brodeur GM. The tumour suppressor CHD5 forms a NuRD-type chromatin remodelling complex. Biochem J. 2015;468(2):345–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Koyama H, Zhuang T, Light JE, Kolla V, Higashi M, McGrady PW, London WB, Brodeur GM. Mechanisms of CHD5 Inactivation in neuroblastomas. Clin Cancer Res. 2012;18(6):1588–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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(13):940–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Liu Z, Yang X, Li Z, McMahon C, Sizer C, Barenboim-Stapleton L, Bliskovsky V, Mock B, Ried T, London WB, Maris J, Khan J, Thiele CJ. CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression. Cell Death Differ. 2011;18(7):1174–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu Z, Naranjo A, Thiele CJ. CASZ1b, the short isoform of CASZ1 gene, coexpresses with CASZ1a during neurogenesis and suppresses neuroblastoma cell growth. PLoS One. 2011;6(4):e18557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang C, Liu Z, Woo CW, Li Z, Wang L, Wei JS, Marquez VE, Bates SE, Jin Q, Khan J, Ge K, Thiele CJ. EZH2 Mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR. Cancer Res. 2012;72(1):315–24.

    Article  CAS  PubMed  Google Scholar 

  64. Liu Z, Lam N, Thiele CJ. Zinc finger transcription factor CASZ1 interacts with histones, DNA repair proteins and recruits NuRD complex to regulate gene transcription. Oncotarget. 2015;6(29):27628–40.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Henrich KO, Bauer T, Schulte J, Ehemann V, Deubzer H, Gogolin S, Muth D, Fischer M, Benner A, Konig R, Schwab M, Westermann F. CAMTA1, a 1p36 tumor suppressor candidate, inhibits growth and activates differentiation programs in neuroblastoma cells. Cancer Res. 2011;71(8):3142–51.

    Article  CAS  PubMed  Google Scholar 

  66. 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(36):24426–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Schlisio S, Kenchappa RS, Vredeveld LC, George RE, Stewart R, Greulich H, Shahriari K, Nguyen NV, Pigny P, Dahia PL, Pomeroy SL, Maris JM, Look AT, Meyerson M, Peeper DS, Carter BD, et al. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 2008;22(7):884–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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(39):5204–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Welch C, Chen Y, Stallings RL. MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene. 2007;26(34):5017–22.

    Article  CAS  PubMed  Google Scholar 

  70. Guo C, White PS, Weiss MJ, Hogarty MD, Thompson PM, Stram DO, Gerbing R, Matthay KK, Seeger RC, Brodeur GM, Maris JM. Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Oncogene. 1999;18(35):4948–57.

    Article  CAS  PubMed  Google Scholar 

  71. Caren H, Kryh H, Nethander M, Sjoberg RM, Trager C, Nilsson S, Abrahamsson J, Kogner P, Martinsson T. High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. Proc Natl Acad Sci U S A. 2010;107(9):4323–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Maris JM, Guo C, White PS, Hogarty MD, Thompson PM, Stram DO, Gerbing R, Matthay KK, Seeger RC, Brodeur GM. Allelic deletion at chromosome bands 11q14-23 is common in neuroblastoma. Med Pediatr Oncol. 2001;36(1):24–7.

    Article  CAS  PubMed  Google Scholar 

  73. Mandriota SJ, Valentijn LJ, Lesne L, Betts DR, Marino D, Boudal-Khoshbeen M, London WB, Rougemont AL, Attiyeh EF, Maris JM, Hogarty MD, Koster J, Molenaar JJ, Versteeg R, Ansari M, Gumy-Pause F. Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism. Oncotarget. 2015;6(21):18558–76.

    Article  PubMed  PubMed Central  Google Scholar 

  74. 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(9):2087–94.

    Article  CAS  PubMed  Google Scholar 

  75. 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(23):3329–38.

    Article  CAS  PubMed  Google Scholar 

  76. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. 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, et al. Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med. 1999;340(25):1954–61.

    Article  CAS  PubMed  Google Scholar 

  78. 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(3):156–65.

    Article  CAS  PubMed  Google Scholar 

  79. Bown N, Lastowska M, Cotterill S, O’Neill S, Ellershaw C, Roberts P, Lewis I, Pearson AD, Group UKCC and the UKCsCSG. 17q gain in neuroblastoma predicts adverse clinical outcome. U.K. Cancer Cytogenetics Group and the U.K. Children’s Cancer Study Group. Med Pediatr Oncol. 2001;36(1):14–9.

    Article  CAS  PubMed  Google Scholar 

  80. Kuzyk A, Booth S, Righolt C, Mathur S, Gartner J, Mai S. MYCN overexpression is associated with unbalanced copy number gain, altered nuclear location, and overexpression of chromosome arm 17q genes in neuroblastoma tumors and cell lines. Genes Chromosomes Cancer. 2015;54(10):616–28.

    Article  CAS  PubMed  Google Scholar 

  81. Hagenbuchner J, Kiechl-Kohlendorfer U, Obexer P, Ausserlechner MJ. BIRC5/Survivin as a target for glycolysis inhibition in high-stage neuroblastoma. Oncogene. 2015;35:2052–61.

    Article  PubMed  CAS  Google Scholar 

  82. Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E, Ohira M, Hashizume K, Kobayashi H, Kaneko Y, Nakagawara A. High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene. 2000;19(5):617–23.

    Article  CAS  PubMed  Google Scholar 

  83. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144(1):27–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kloosterman WP, Koster J, Molenaar JJ. Prevalence and clinical implications of chromothripsis in cancer genomes. Curr Opin Oncol. 2014;26(1):64–72.

    Article  CAS  PubMed  Google Scholar 

  85. 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(1):99–105.

    Article  PubMed  Google Scholar 

  86. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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, et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008;455(7215):930–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 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(7215):967–70.

    Article  CAS  PubMed  Google Scholar 

  89. George RE, Sanda T, Hanna M, Frohling S, Luther 2nd W, Zhang J, Ahn Y, Zhou W, London WB, McGrady P, Xue L, Zozulya S, Gregor VE, Webb TR, Gray NS, Gilliland DG, et al. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature. 2008;455(7215):975–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 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(7215):971–4.

    Article  CAS  PubMed  Google Scholar 

  91. Bresler SC, Weiser DA, Huwe PJ, Park JH, Krytska K, Ryles H, Laudenslager M, Rappaport EF, Wood AC, McGrady PW, Hogarty MD, London WB, Radhakrishnan R, Lemmon MA, Mosse YP. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell. 2014;26(5):682–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene. 1997;14(4):439–49.

    Article  CAS  PubMed  Google Scholar 

  93. Webb TR, Slavish J, George RE, Look AT, Xue L, Jiang Q, Cui X, Rentrop WB, Morris SW. Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy. Expert Rev Anticancer Ther. 2009;9(3):331–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bazigou E, Apitz H, Johansson J, Loren CE, Hirst EM, Chen PL, Palmer RH, Salecker I. Anterograde Jelly belly and Alk receptor tyrosine kinase signaling mediates retinal axon targeting in Drosophila. Cell. 2007;128(5):961–75.

    Article  CAS  PubMed  Google Scholar 

  95. Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8(1):11–23.

    Article  CAS  PubMed  Google Scholar 

  96. Hallberg B, Palmer RH. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer. 2013;13(10):685–700.

    Article  CAS  PubMed  Google Scholar 

  97. Souttou B, Carvalho NB, Raulais D, Vigny M. Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway. J Biol Chem. 2001;276(12):9526–31.

    Article  CAS  PubMed  Google Scholar 

  98. Azarova AM, Gautam G, George RE. Emerging importance of ALK in neuroblastoma. Semin Cancer Biol. 2011;21(4):267–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. de Pontual L, Kettaneh D, Gordon CT, Oufadem M, Boddaert N, Lees M, Balu L, Lachassinne E, Petros A, Mollet J, Wilson LC, Munnich A, Brugiere L, Delattre O, Vekemans M, Etchevers H, et al. Germline gain-of-function mutations of ALK disrupt central nervous system development. Hum Mutat. 2011;32(3):272–6.

    Article  PubMed  Google Scholar 

  100. 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(4):459–61.

    Article  CAS  PubMed  Google Scholar 

  101. Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, Marazita ML. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Am J Med Genet A. 2003;123A(3):267–78.

    Article  PubMed  Google Scholar 

  102. 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(4):727–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 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(4):761–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bachetti T, Di Paolo D, Di Lascio S, Mirisola V, Brignole C, Bellotti M, Caffa I, Ferraris C, Fiore M, Fornasari D, Chiarle R, Borghini S, Pfeffer U, Ponzoni M, Ceccherini I, Perri P. PHOX2B-mediated regulation of ALK expression: in vitro identification of a functional relationship between two genes involved in neuroblastoma. PLoS One. 2010;5(10):e13108:1–15

    Google Scholar 

  105. Pattyn A, Goridis C, Brunet JF. Specification of the central noradrenergic phenotype by the homeobox gene Phox2b. Mol Cell Neurosci. 2000;15(3):235–43.

    Article  CAS  PubMed  Google Scholar 

  106. Pei D, Luther W, Wang W, Paw BH, Stewart RA, George RE. Distinct neuroblastoma-associated alterations of PHOX2B impair sympathetic neuronal differentiation in zebrafish models. PLoS Genet. 2013;9(6):e1003533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Raabe EH, Laudenslager M, Winter C, Wasserman N, Cole K, LaQuaglia M, Maris DJ, Mosse YP, Maris JM. Prevalence and functional consequence of PHOX2B mutations in neuroblastoma. Oncogene. 2008;27(4):469–76.

    Article  CAS  PubMed  Google Scholar 

  108. Nagashimada M, Ohta H, Li C, Nakao K, Uesaka T, Brunet JF, Amiel J, Trochet D, Wakayama T, Enomoto H. Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression. J Clin Invest. 2012;122(9):3145–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Heukamp LC, Thor T, Schramm A, De Preter K, Kumps C, De Wilde B, Odersky A, Peifer M, Lindner S, Spruessel A, Pattyn F, Mestdagh P, Menten B, Kuhfittig-Kulle S, Kunkele A, Konig K, et al. Targeted expression of mutated ALK induces neuroblastoma in transgenic mice. Sci Transl Med. 2012;4(141):141ra191.

    Article  CAS  Google Scholar 

  110. Berry T, Luther W, Bhatnagar N, Jamin Y, Poon E, Sanda T, Pei D, Sharma B, Vetharoy WR, Hallsworth A, Ahmad Z, Barker K, Moreau L, Webber H, Wang W, Liu Q, et al. The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell. 2012;22(1):117–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhu S, Lee JS, Guo F, Shin J, Perez-Atayde AR, Kutok JL, Rodig SJ, Neuberg DS, Helman D, Feng H, Stewart RA, Wang W, George RE, Kanki JP, Look AT. Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer Cell. 2012;21(3):362–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Liu Z, Thiele CJ. ALK and MYCN: when two oncogenes are better than one. Cancer Cell. 2012;21(3):325–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Umapathy G, El Wakil A, Witek B, Chesler L, Danielson L, Deng X, Gray NS, Johansson M, Kvarnbrink S, Ruuth K, Schonherr C, Palmer RH, Hallberg B. The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma. Sci Signal. 2014;7(349):ra102.

    Article  PubMed  CAS  Google Scholar 

  114. Cheung NK, Dyer MA. Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer. 2013;13(6):397–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Fishbein L, Khare S, Wubbenhorst B, DeSloover D, D’Andrea K, Merrill S, Cho NW, Greenberg RA, Else T, Montone K, LiVolsi V, Fraker D, Daber R, Cohen DL, Nathanson KL. Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun. 2015;6:6140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz Jr LA, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, de Lange T, De S, Petrini JH, Sung PA, Jasin M, Rosenbluh J, Zwang Y, Weir BA, Hatton C, Ivanova E, Macconaill L, et al. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet. 2012;8(7):e1002772.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wang X, Nagl NG, Wilsker D, Van Scoy M, Pacchione S, Yaciuk P, Dallas PB, Moran E. Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. Biochem J. 2004;383(Pt 2):319–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wu RC, Wang TL, Shih IM. The emerging roles of ARID1A in tumor suppression. Cancer Biol Ther. 2014;15(6):655–64.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Takeda T, Banno K, Okawa R, Yanokura M, Iijima M, Irie-Kunitomi H, Nakamura K, Iida M, Adachi M, Umene K, Nogami Y, Masuda K, Kobayashi Y, Tominaga E, Aoki D. ARID1A gene mutation in ovarian and endometrial cancers (Review). Oncol Rep. 2015;35:607–13.

    PubMed  PubMed Central  Google Scholar 

  121. Park JH, Park EJ, Lee HS, Kim SJ, Hur SK, Imbalzano AN, Kwon J. Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX induction. EMBO J. 2006;25(17):3986–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hara R, Sancar A. The SWI/SNF chromatin-remodeling factor stimulates repair by human excision nuclease in the mononucleosome core particle. Mol Cell Biol. 2002;22(19):6779–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jones S, Wang TL, Shih Ie M, Mao TL, Nakayama K, Roden R, Glas R, Slamon D, Diaz Jr LA, Vogelstein B, Kinzler KW, Velculescu VE, Papadopoulos N. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 2010;330(6001):228–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wu JN, Roberts CW. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov. 2013;3(1):35–43.

    Article  CAS  PubMed  Google Scholar 

  125. Cajuso T, Hanninen UA, Kondelin J, Gylfe AE, Tanskanen T, Katainen R, Pitkanen E, Ristolainen H, Kaasinen E, Taipale M, Taipale J, Bohm J, Renkonen-Sinisalo L, Mecklin JP, Jarvinen H, Tuupanen S, et al. Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer. Int J Cancer. 2014;135(3):611–23.

    Article  CAS  PubMed  Google Scholar 

  126. Khursheed M, Kolla JN, Kotapalli V, Gupta N, Gowrishankar S, Uppin SG, Sastry RA, Koganti S, Sundaram C, Pollack JR, Bashyam MD. ARID1B, a member of the human SWI/SNF chromatin remodeling complex, exhibits tumour-suppressor activities in pancreatic cancer cell lines. Br J Cancer. 2013;108(10):2056–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Eleveld TF, Oldridge DA, Bernard V, Koster J, Daage LC, Diskin SJ, Schild L, Bentahar NB, Bellini A, Chicard M, Lapouble E, Combaret V, Legoix-Ne P, Michon J, Pugh TJ, Hart LS, et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet. 2015;47(8):864–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Schramm A, Koster J, Assenov Y, Althoff K, Peifer M, Mahlow E, Odersky A, Beisser D, Ernst C, Henssen AG, Stephan H, Schroder C, Heukamp L, Engesser A, Kahlert Y, Theissen J, et al. Mutational dynamics between primary and relapse neuroblastomas. Nat Genet. 2015;47(8):872–7.

    Article  CAS  PubMed  Google Scholar 

  129. Diskin SJ, Capasso M, Schnepp RW, Cole KA, Attiyeh EF, Hou C, Diamond M, Carpenter EL, Winter C, Lee H, Jagannathan J, Latorre V, Iolascon A, Hakonarson H, Devoto M, Maris JM. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat Genet. 2012;44(10):1126–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Schnepp RW, Khurana P, Attiyeh EF, Raman P, Chodosh SE, Oldridge DA, Gagliardi ME, Conkrite KL, Asgharzadeh S, Seeger RC, Madison BB, Rustgi AK, Maris JM, Diskin SJ. A LIN28B-RAN-AURKA signaling network promotes neuroblastoma tumorigenesis. Cancer Cell. 2015;28(5):599–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Molenaar JJ, Domingo-Fernandez R, Ebus ME, Lindner S, Koster J, Drabek K, Mestdagh P, van Sluis P, Valentijn LJ, van Nes J, Broekmans M, Haneveld F, Volckmann R, Bray I, Heukamp L, Sprussel A, et al. LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nat Genet. 2012;44(11):1199–206.

    Article  CAS  PubMed  Google Scholar 

  132. Oldridge DA, Wood AC, Weichert-Leahey N, Crimmins I, Sussman R, Winter C, McDaniel LD, Diamond M, Hart LS, Zhu S, Durbin AD, Abraham BJ, Anders L, Tian L, Zhang S, Wei JS, et al. Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature. 2015;528:418–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wang K, Diskin SJ, Zhang H, Attiyeh EF, Winter C, Hou C, Schnepp RW, Diamond M, Bosse K, Mayes PA, Glessner J, Kim C, Frackelton E, Garris M, Wang Q, Glaberson W, et al. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature. 2011;469(7329):216–20.

    Article  CAS  PubMed  Google Scholar 

  134. Bosse KR, Diskin SJ, Cole KA, Wood AC, Schnepp RW, Norris G, le Nguyen B, Jagannathan J, Laquaglia M, Winter C, Diamond M, Hou C, Attiyeh EF, Mosse YP, Pineros V, Dizin E, et al. Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity. Cancer Res. 2012;72(8):2068–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 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, et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med. 2008;358(24):2585–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Capasso M, Diskin S, Cimmino F, Acierno G, Totaro F, Petrosino G, Pezone L, Diamond M, McDaniel L, Hakonarson H, Iolascon A, Devoto M, Maris JM. Common genetic variants in NEFL influence gene expression and neuroblastoma risk. Cancer Res. 2014;74(23):6913–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Capasso M, Diskin SJ, Totaro F, Longo L, De Mariano M, Russo R, Cimmino F, Hakonarson H, Tonini GP, Devoto M, Maris JM, Iolascon A. Replication of GWAS-identified neuroblastoma risk loci strengthens the role of BARD1 and affirms the cumulative effect of genetic variations on disease susceptibility. Carcinogenesis. 2013;34(3):605–11.

    Article  CAS  PubMed  Google Scholar 

  138. Diskin SJ, Hou C, Glessner JT, Attiyeh EF, Laudenslager M, Bosse K, Cole K, Mosse YP, Wood A, Lynch JE, Pecor K, Diamond M, Winter C, Wang K, Kim C, Geiger EA, et al. Copy number variation at 1q21.1 associated with neuroblastoma. Nature. 2009;459(7249):987–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Latorre V, Diskin SJ, Diamond MA, Zhang H, Hakonarson H, Maris JM, Devoto M. Replication of neuroblastoma SNP association at the BARD1 locus in African-Americans. Cancer Epidemiol Biomarkers Prev. 2012;21(4):658–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Irminger-Finger I, Jefford CE. Is there more to BARD1 than BRCA1? Nat Rev Cancer. 2006;6(5):382–91.

    Article  CAS  PubMed  Google Scholar 

  141. Zhou J, Ng SB, Chng WJ. LIN28/LIN28B: an emerging oncogenic driver in cancer stem cells. Int J Biochem Cell Biol. 2013;45(5):973–8.

    Article  CAS  PubMed  Google Scholar 

  142. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell. 2009;139(4):693–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. West JA, Viswanathan SR, Yabuuchi A, Cunniff K, Takeuchi A, Park IH, Sero JE, Zhu H, Perez-Atayde A, Frazier AL, Surani MA, Daley GQ. A role for Lin28 in primordial germ-cell development and germ-cell malignancy. Nature. 2009;460(7257):909–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Beckers A, Van Peer G, Carter DR, Gartlgruber M, Herrmann C, Agarwal S, Helsmoortel HH, Althoff K, Molenaar JJ, Cheung BB, Schulte JH, Benoit Y, Shohet JM, Westermann F, Marshall GM, Vandesompele J, et al. MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma. Cancer Lett. 2015;366(1):123–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lu J, Chu P, Wang H, Jin Y, Han S, Han W, Tai J, Guo Y, Ni X. Candidate gene association analysis of neuroblastoma in Chinese children strengthens the role of LMO1. PLoS One. 2015;10(6):e0127856.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Lin YW, Deveney R, Barbara M, Iscove NN, Nimer SD, Slape C, Aplan PD. OLIG2 (BHLHB1), a bHLH transcription factor, contributes to leukemogenesis in concert with LMO1. Cancer Res. 2005;65(16):7151–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Chervinsky DS, Lam DH, Melman MP, Gross KW, Aplan PD. scid Thymocytes with TCRbeta gene rearrangements are targets for the oncogenic effect of SCL and LMO1 transgenes. Cancer Res. 2001;61(17):6382–7.

    CAS  PubMed  Google Scholar 

  148. Chervinsky DS, Zhao XF, Lam DH, Ellsworth M, Gross KW, Aplan PD. Disordered T-cell development and T-cell malignancies in SCL LMO1 double-transgenic mice: parallels with E2A-deficient mice. Mol Cell Biol. 1999;19(7):5025–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–74.

    Article  CAS  PubMed  Google Scholar 

  150. Chen Y, Stallings RL. Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis, differentiation, and apoptosis. Cancer Res. 2007;67(3):976–83.

    Article  CAS  PubMed  Google Scholar 

  151. 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(3):699–704.

    Article  CAS  PubMed  Google Scholar 

  152. Bray I, Bryan K, Prenter S, Buckley PG, Foley NH, Murphy DM, Alcock L, Mestdagh P, Vandesompele J, Speleman F, London WB, McGrady PW, Higgins DG, O’Meara A, O’Sullivan M, Stallings RL. Widespread dysregulation of MiRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival. PLoS One. 2009;4(11):e7850.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Mestdagh P, Fredlund E, Pattyn F, Schulte JH, Muth D, Vermeulen J, Kumps C, Schlierf S, De Preter K, Van Roy N, Noguera R, Laureys G, Schramm A, Eggert A, Westermann F, Speleman F, et al. MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors. Oncogene. 2010;29(9):1394–404.

    Article  CAS  PubMed  Google Scholar 

  154. Lin RJ, Lin YC, Chen J, Kuo HH, Chen YY, Diccianni MB, London WB, Chang CH, Yu AL. microRNA signature and expression of Dicer and Drosha can predict prognosis and delineate risk groups in neuroblastoma. Cancer Res. 2010;70(20):7841–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. De Preter K, Mestdagh P, Vermeulen J, Zeka F, Naranjo A, Bray I, Castel V, Chen C, Drozynska E, Eggert A, Hogarty MD, Izycka-Swieszewska E, London WB, Noguera R, Piqueras M, Bryan K, et al. miRNA expression profiling enables risk stratification in archived and fresh neuroblastoma tumor samples. Clin Cancer Res. 2011;17(24):7684–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Zhi F, Wang R, Wang Q, Xue L, Deng D, Wang S, Yang Y. MicroRNAs in neuroblastoma: small-sized players with a large impact. Neurochem Res. 2014;39(4):613–23.

    Article  CAS  PubMed  Google Scholar 

  157. Xiang X, Mei H, Zhao X, Pu J, Li D, Qu H, Jiao W, Zhao J, Huang K, Zheng L, Tong Q. miRNA-337-3p suppresses neuroblastoma progression by repressing the transcription of matrix metalloproteinase 14. Oncotarget. 2015;6(26):22452–66.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Xiang X, Mei H, Qu H, Zhao X, Li D, Song H, Jiao W, Pu J, Huang K, Zheng L, Tong Q. miRNA-584-5p exerts tumor suppressive functions in human neuroblastoma through repressing transcription of matrix metalloproteinase 14. Biochim Biophys Acta. 2015;1852(9):1743–54.

    Article  CAS  PubMed  Google Scholar 

  159. Wu K, Yang L, Chen J, Zhao H, Wang J, Xu S, Huang Z. miR-362-5p inhibits proliferation and migration of neuroblastoma cells by targeting phosphatidylinositol 3-kinase-C2beta. FEBS Lett. 2015;589(15):1911–9.

    Article  CAS  PubMed  Google Scholar 

  160. Althoff K, Lindner S, Odersky A, Mestdagh P, Beckers A, Karczewski S, Molenaar JJ, Bohrer A, Knauer S, Speleman F, Epple M, Kozlova D, Yoon S, Baek K, Vandesompele J, Eggert A, et al. miR-542-3p exerts tumor suppressive functions in neuroblastoma by downregulating Survivin. Int J Cancer. 2015;136(6):1308–20.

    Article  CAS  PubMed  Google Scholar 

  161. Zhang H, Liu T, Yi S, Gu L, Zhou M. Targeting MYCN IRES in MYCN-amplified neuroblastoma with miR-375 inhibits tumor growth and sensitizes tumor cells to radiation. Mol Oncol. 2015;9(7):1301–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Qu H, Zheng L, Pu J, Mei H, Xiang X, Zhao X, Li D, Li S, Mao L, Huang K, Tong Q. miRNA-558 promotes tumorigenesis and aggressiveness of neuroblastoma cells through activating the transcription of heparanase. Hum Mol Genet. 2015;24(9):2539–51.

    Article  CAS  PubMed  Google Scholar 

  163. Li Y, Li W, Zhang JG, Li HY, Li YM. Downregulation of tumor suppressor menin by miR-421 promotes proliferation and migration of neuroblastoma. Tumour Biol. 2014;35(10):10011–7.

    Article  CAS  PubMed  Google Scholar 

  164. Cole KA, Attiyeh EF, Mosse YP, Laquaglia MJ, Diskin SJ, Brodeur GM, Maris JM. A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Mol Cancer Res. 2008;6(5):735–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 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(5):e2236.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Mestdagh P, Bostrom AK, Impens F, Fredlund E, Van Peer G, De Antonellis P, von Stedingk K, Ghesquiere B, Schulte S, Dews M, Thomas-Tikhonenko A, Schulte JH, Zollo M, Schramm A, Gevaert K, Axelson H, et al. The miR-17-92 microRNA cluster regulates multiple components of the TGF-beta pathway in neuroblastoma. Mol Cell. 2010;40(5):762–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. De Brouwer S, Mestdagh P, Lambertz I, Pattyn F, De Paepe A, Westermann F, Schroeder C, Schulte JH, Schramm A, De Preter K, Vandesompele J, Speleman F. Dickkopf-3 is regulated by the MYCN-induced miR-17-92 cluster in neuroblastoma. Int J Cancer. 2012;130(11):2591–8.

    Article  PubMed  CAS  Google Scholar 

  168. Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, Barrette TR, Prensner JR, Evans JR, Zhao S, Poliakov A, Cao X, Dhanasekaran SM, Wu YM, Robinson DR, Beer DG, et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 2015;47(3):199–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155–9.

    Article  CAS  PubMed  Google Scholar 

  170. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, Nagano T, Mancini-Dinardo D, Kanduri C. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell. 2008;32(2):232–46.

    Article  CAS  PubMed  Google Scholar 

  172. Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 2011;10:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Bejerano G, Pheasant M, Makunin I, Stephen S, Kent WJ, Mattick JS, Haussler D. Ultraconserved elements in the human genome. Science. 2004;304(5675):1321–5.

    Article  CAS  PubMed  Google Scholar 

  174. Scaruffi P, Stigliani S, Moretti S, Coco S, De Vecchi C, Valdora F, Garaventa A, Bonassi S, Tonini GP. Transcribed-Ultra Conserved Region expression is associated with outcome in high-risk neuroblastoma. BMC Cancer. 2009;9:441.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Watters KM, Bryan K, Foley NH, Meehan M, Stallings RL. Expressional alterations in functional ultra-conserved non-coding RNAs in response to all-trans retinoic acid--induced differentiation in neuroblastoma cells. BMC Cancer. 2013;13:184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Bertone P, Stolc V, Royce TE, Rozowsky JS, Urban AE, Zhu X, Rinn JL, Tongprasit W, Samanta M, Weissman S, Gerstein M, Snyder M. Global identification of human transcribed sequences with genome tiling arrays. Science. 2004;306(5705):2242–6.

    Article  CAS  PubMed  Google Scholar 

  178. Russell MR, Penikis A, Oldridge DA, Alvarez-Dominguez JR, McDaniel L, Diamond M, Padovan O, Raman P, Li Y, Wei JS, Zhang S, Gnanchandran J, Seeger R, Asgharzadeh S, Khan J, Diskin SJ, et al. CASC15-S is a tumor suppressor lncRNA at the 6p22 neuroblastoma susceptibility locus. Cancer Res. 2015;75(15):3155–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Pandey GK, Mitra S, Subhash S, Hertwig F, Kanduri M, Mishra K, Fransson S, Ganeshram A, Mondal T, Bandaru S, Ostensson M, Akyurek LM, Abrahamsson J, Pfeifer S, Larsson E, Shi L, et al. The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation. Cancer Cell. 2014;26(5):722–37.

    Article  CAS  PubMed  Google Scholar 

  180. Liu PY, Erriquez D, Marshall GM, Tee AE, Polly P, Wong M, Liu B, Bell JL, Zhang XD, Milazzo G, Cheung BB, Fox A, Swarbrick A, Huttelmaier S, Kavallaris M, Perini G. Effects of a novel long noncoding RNA, lncUSMycN, on N-Myc expression and neuroblastoma progression. J Natl Cancer Inst. 2014;106(7):dju113.

    Article  PubMed  CAS  Google Scholar 

  181. Pandey GK, Kanduri C. Long noncoding RNAs and neuroblastoma. Oncotarget. 2015;6(21):18265–75.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Boumber Y, Issa JP. Epigenetics in cancer: what’s the future? Oncology (Williston Park). 2011;25(3):220–6, 228.

    Google Scholar 

  183. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Decock A, Ongenaert M, Cannoodt R, Verniers K, De Wilde B, Laureys G, Van Roy N, Berbegall AP, Bienertova-Vasku J, Bown N, Clement N, Combaret V, Haber M, Hoyoux C, Murray J, Noguera R, et al. Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma. Oncotarget. 2015;7(2):1960–72.

    PubMed Central  Google Scholar 

  185. 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(16):1208–19.

    Article  CAS  PubMed  Google Scholar 

  186. Asada K, Abe M, Ushijima T. Clinical application of the CpG island methylator phenotype to prognostic diagnosis in neuroblastomas. J Hum Genet. 2013;58(7):428–33.

    Article  CAS  PubMed  Google Scholar 

  187. Astuti D, Agathanggelou A, Honorio S, Dallol A, Martinsson T, Kogner P, Cummins C, Neumann HP, Voutilainen R, Dahia P, Eng C, Maher ER, Latif F. RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours. Oncogene. 2001;20(51):7573–7.

    Article  CAS  PubMed  Google Scholar 

  188. Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med. 2000;6(5):529–35.

    Article  CAS  PubMed  Google Scholar 

  189. Gonzalez-Gomez P, Bello MJ, Lomas J, Arjona D, Alonso ME, Aminoso C, Lopez-Marin I, Anselmo NP, Sarasa JL, Gutierrez M, Casartelli C, Rey JA. Aberrant methylation of multiple genes in neuroblastic tumours. relationship with MYCN amplification and allelic status at 1p. Eur J Cancer. 2003;39(10):1478–85.

    Article  CAS  PubMed  Google Scholar 

  190. Witt O, Deubzer HE, Lodrini M, Milde T, Oehme I. Targeting histone deacetylases in neuroblastoma. Curr Pharm Des. 2009;15(4):436–47.

    Article  CAS  PubMed  Google Scholar 

  191. Oehme I, Deubzer HE, Wegener D, Pickert D, Linke JP, Hero B, Kopp-Schneider A, Westermann F, Ulrich SM, von Deimling A, Fischer M, Witt O. Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res. 2009;15(1):91–9.

    Article  CAS  PubMed  Google Scholar 

  192. Panicker J, Li Z, McMahon C, Sizer C, Steadman K, Piekarz R, Bates SE, Thiele CJ. Romidepsin (FK228/depsipeptide) controls growth and induces apoptosis in neuroblastoma tumor cells. Cell Cycle. 2010;9(9):1830–8.

    Article  CAS  PubMed  Google Scholar 

  193. Delcuve GP, Khan DH, Davie JR. Targeting class I histone deacetylases in cancer therapy. Expert Opin Ther Targets. 2013;17(1):29–41.

    Article  CAS  PubMed  Google Scholar 

  194. Schulte JH, Lim S, Schramm A, Friedrichs N, Koster J, Versteeg R, Ora I, Pajtler K, Klein-Hitpass L, Kuhfittig-Kulle S, Metzger E, Schule R, Eggert A, Buettner R, Kirfel J. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res. 2009;69(5):2065–71.

    Article  CAS  PubMed  Google Scholar 

  195. Cui H, Ma J, Ding J, Li T, Alam G, Ding HF. Bmi-1 regulates the differentiation and clonogenic self-renewal of I-type neuroblastoma cells in a concentration-dependent manner. J Biol Chem. 2006;281(45):34696–704.

    Article  CAS  PubMed  Google Scholar 

  196. Nuchtern JG, London WB, Barnewolt CE, Naranjo A, McGrady PW, Geiger JD, Diller L, Schmidt ML, Maris JM, Cohn SL, Shamberger RC. A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children’s Oncology Group study. Ann Surg. 2012;256(4):573–80.

    Article  PubMed  Google Scholar 

  197. Strother DR, London WB, Schmidt ML, Brodeur GM, Shimada H, Thorner P, Collins MH, Tagge E, Adkins S, Reynolds CP, Murray K, Lavey RS, Matthay KK, Castleberry R, Maris JM, Cohn SL. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641. J Clin Oncol. 2012;30(15):1842–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Perez CA, Matthay KK, Atkinson JB, Seeger RC, Shimada H, Haase GM, Stram DO, Gerbing RB, Lukens JN. Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children’s cancer group study. J Clin Oncol. 2000;18(1):18–26.

    CAS  PubMed  Google Scholar 

  199. Matthay KK, Perez C, Seeger RC, Brodeur GM, Shimada H, Atkinson JB, Black CT, Gerbing R, Haase GM, Stram DO, Swift P, Lukens JN. Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children’s Cancer Group study. J Clin Oncol. 1998;16(4):1256–64.

    CAS  PubMed  Google Scholar 

  200. 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(34):8819–27.

    Article  PubMed  Google Scholar 

  201. Baker DL, Schmidt ML, Cohn SL, Maris JM, London WB, Buxton A, Stram D, Castleberry RP, Shimada H, Sandler A, Shamberger RC, Look AT, Reynolds CP, Seeger RC, Matthay KK, Children’s Oncology G. Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med. 2010;363(14):1313–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Pinto NR, Applebaum MA, Volchenboum SL, Matthay KK, London WB, Ambros PF, Nakagawara A, Berthold F, Schleiermacher G, Park JR, Valteau-Couanet D, Pearson AD, Cohn SL. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015;33(27):3008–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Pearson AD, Pinkerton CR, Lewis IJ, Imeson J, Ellershaw C, Machin D, European Neuroblastoma Study G, Children’s C and Leukaemia G. High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol. 2008;9(3):247–56.

    Article  CAS  PubMed  Google Scholar 

  204. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM, Gerbing RB, Reynolds CP. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med. 1999;341(16):1165–73.

    Article  CAS  PubMed  Google Scholar 

  205. London WB, Castel V, Monclair T, Ambros PF, Pearson AD, Cohn SL, Berthold F, Nakagawara A, Ladenstein RL, Iehara T, Matthay KK. Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol. 2011;29(24):3286–92.

    Article  PubMed  PubMed Central  Google Scholar 

  206. Suzuki M, Cheung NK. Disialoganglioside GD2 as a therapeutic target for human diseases. Expert Opin Ther Targets. 2015;19(3):349–62.

    Article  CAS  PubMed  Google Scholar 

  207. Svennerholm L, Bostrom K, Fredman P, Jungbjer B, Lekman A, Mansson JE, Rynmark BM. Gangliosides and allied glycosphingolipids in human peripheral nerve and spinal cord. Biochim Biophys Acta. 1994;1214(2):115–23.

    Article  CAS  PubMed  Google Scholar 

  208. Lammie G, Cheung N, Gerald W, Rosenblum M, Cordoncardo C. Ganglioside gd(2) expression in the human nervous-system and in neuroblastomas - an immunohistochemical study. Int J Oncol. 1993;3(5):909–15.

    CAS  PubMed  Google Scholar 

  209. Battula VL, Shi Y, Evans KW, Wang RY, Spaeth EL, Jacamo RO, Guerra R, Sahin AA, Marini FC, Hortobagyi G, Mani SA, Andreeff M. Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis. J Clin Invest. 2012;122(6):2066–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Furukawa K, Hamamura K, Ohkawa Y, Ohmi Y, Furukawa K. Disialyl gangliosides enhance tumor phenotypes with differential modalities. Glycoconj J. 2012;29(8-9):579–84.

    Article  CAS  PubMed  Google Scholar 

  211. Julien S, Bobowski M, Steenackers A, Le Bourhis X, Delannoy P. How Do gangliosides regulate RTKs signaling? Cells. 2013;2(4):751–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Shibuya H, Hamamura K, Hotta H, Matsumoto Y, Nishida Y, Hattori H, Furukawa K, Ueda M, Furukawa K. Enhancement of malignant properties of human osteosarcoma cells with disialyl gangliosides GD2/GD3. Cancer Sci. 2012;103(9):1656–64.

    Article  CAS  PubMed  Google Scholar 

  213. Probstmeier R, Pesheva P. Tenascin-C inhibits beta1 integrin-dependent cell adhesion and neurite outgrowth on fibronectin by a disialoganglioside-mediated signaling mechanism. Glycobiology. 1999;9(2):101–14.

    Article  CAS  PubMed  Google Scholar 

  214. Cheung NK, Saarinen UM, Neely JE, Landmeier B, Donovan D, Coccia PF. Monoclonal antibodies to a glycolipid antigen on human neuroblastoma cells. Cancer Res. 1985;45(6):2642–9.

    CAS  PubMed  Google Scholar 

  215. Thurin J, Thurin M, Kimoto Y, Herlyn M, Lubeck MD, Elder DE, Smereczynska M, Karlsson KA, Clark Jr WM, Steplewski Z, et al. Monoclonal antibody-defined correlations in melanoma between levels of GD2 and GD3 antigens and antibody-mediated cytotoxicity. Cancer Res. 1987;47(5):1229–33.

    CAS  PubMed  Google Scholar 

  216. Mujoo K, Cheresh DA, Yang HM, Reisfeld RA. Disialoganglioside GD2 on human neuroblastoma cells: target antigen for monoclonal antibody-mediated cytolysis and suppression of tumor growth. Cancer Res. 1987;47(4):1098–104.

    CAS  PubMed  Google Scholar 

  217. Cheung NK, Cheung IY, Kushner BH, Ostrovnaya I, Chamberlain E, Kramer K, Modak S. Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J Clin Oncol. 2012;30(26):3264–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Streby KA, Shah N, Ranalli MA, Kunkler A, Cripe TP. Nothing but NET: a review of norepinephrine transporter expression and efficacy of 131I-mIBG therapy. Pediatr Blood Cancer. 2015;62(1):5–11.

    Article  CAS  PubMed  Google Scholar 

  220. DuBois SG, Matthay KK. Radiolabeled metaiodobenzylguanidine for the treatment of neuroblastoma. Nucl Med Biol. 2008;35 Suppl 1:S35–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Matthay KK, Yanik G, Messina J, Quach A, Huberty J, Cheng SC, Veatch J, Goldsby R, Brophy P, Kersun LS, Hawkins RA, Maris JM. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol. 2007;25(9):1054–60.

    Article  CAS  PubMed  Google Scholar 

  222. Polishchuk AL, Dubois SG, Haas-Kogan D, Hawkins R, Matthay KK. Response, survival, and toxicity after iodine-131-metaiodobenzylguanidine therapy for neuroblastoma in preadolescents, adolescents, and adults. Cancer. 2011;117(18):4286–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Matthay KK, DeSantes K, Hasegawa B, Huberty J, Hattner RS, Ablin A, Reynolds CP, Seeger RC, Weinberg VK, Price D. Phase I dose escalation of 131I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. J Clin Oncol. 1998;16(1):229–36.

    CAS  PubMed  Google Scholar 

  224. Kraal KC, Tytgat GA, van Eck-Smit BL, Kam B, Caron HN, van Noesel M. Upfront treatment of high-risk neuroblastoma with a combination of 131I-MIBG and topotecan. Pediatr Blood Cancer. 2015;62(11):1886–91.

    Article  CAS  PubMed  Google Scholar 

  225. Ou SH, Bartlett CH, Mino-Kenudson M, Cui J, Iafrate AJ. Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist. 2012;17(11):1351–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Bresler SC, Wood AC, Haglund EA, Courtright J, Belcastro LT, Plegaria JS, Cole K, Toporovskaya Y, Zhao H, Carpenter EL, Christensen JG, Maris JM, Lemmon MA, Mosse YP. Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci Transl Med. 2011;3(108):108ra114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  227. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA, Varella-Garcia M, Camidge DR. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18(5):1472–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Mosse YP, Lim MS, Voss SD, Wilner K, Ruffner K, Laliberte J, Rolland D, Balis FM, Maris JM, Weigel BJ, Ingle AM, Ahern C, Adamson PC, Blaney SM. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013;14(6):472–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014;12(7):429–39.

    PubMed  PubMed Central  Google Scholar 

  230. Infarinato NR, Park JH, Krytska K, Ryles HT, Sano R, Szigety KM, Li Y, Zou HY, Lee NV, Smeal T, Lemmon MA, Mosse YP. The ALK/ROS1 inhibitor PF-06463922 overcomes primary resistance to crizotinib in ALK-driven neuroblastoma. Cancer Discov. 2015;6:96–107.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  231. Carpenter EL, Haglund EA, Mace EM, Deng D, Martinez D, Wood AC, Chow AK, Weiser DA, Belcastro LT, Winter C, Bresler SC, Vigny M, Mazot P, Asgharzadeh S, Seeger RC, Zhao H, et al. Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. Oncogene. 2012;31(46):4859–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Thiele CJ, Reynolds CP, Israel MA. Decreased expression of N-myc precedes retinoic acid-induced morphological differentiation of human neuroblastoma. Nature. 1985;313(6001):404–6.

    Article  CAS  PubMed  Google Scholar 

  233. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin North Am. 2008;55(1):97–120, x.

    Article  PubMed  Google Scholar 

  234. Prochownik EV, Vogt PK. Therapeutic targeting of Myc. Genes Cancer. 2010;1(6):650–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Zirath H, Frenzel A, Oliynyk G, Segerstrom L, Westermark UK, Larsson K, Munksgaard Persson M, Hultenby K, Lehtio J, Einvik C, Pahlman S, Kogner P, Jakobsson PJ, Henriksson MA. MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells. Proc Natl Acad Sci U S A. 2013;110(25):10258–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, Chanthery YH, Nekritz EA, Zeid R, Gustafson WC, Greninger P, Garnett MJ, McDermott U, Benes CH, Kung AL, Weiss WA, Bradner JE, et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013;3(3):308–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Henssen AG, Althoff K, Odersky A, Beckers A, Koche R, Speleman F, Schaefer S, Bell E, Nortmeyer M, Westermann F, De Preter K, Florin A, Heukamp L, Spruessel A, Astrahanseff K, Lindner S, et al. Targeting MYCN-driven transcription by BET-bromodomain inhibition. Clin Cancer Res. 2015;22(10):2470–81.

    Article  PubMed  CAS  Google Scholar 

  238. Chipumuro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T, Hatheway CM, Abraham BJ, Sharma B, Yeung C, Altabef A, Perez-Atayde A, Wong KK, Yuan GC, Gray NS, Young RA, George RE. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell. 2014;159(5):1126–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Hnisz D, Schuijers J, Lin CY, Weintraub AS, Abraham BJ, Lee TI, Bradner JE, Young RA. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol Cell. 2015;58(2):362–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. 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(1):67–78.

    Article  CAS  PubMed  Google Scholar 

  241. Gustafson WC, Meyerowitz JG, Nekritz EA, Chen J, Benes C, Charron E, Simonds EF, Seeger R, Matthay KK, Hertz NT, Eilers M, Shokat KM, Weiss WA. Drugging MYCN through an allosteric transition in Aurora kinase A. Cancer Cell. 2014;26(3):414–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Chesler L, Schlieve C, Goldenberg DD, Kenney A, Kim G, McMillan A, Matthay KK, Rowitch D, Weiss WA. Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Cancer Res. 2006;66(16):8139–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Holzel M, Huang S, Koster J, Ora I, Lakeman A, Caron H, Nijkamp W, Xie J, Callens T, Asgharzadeh S, Seeger RC, Messiaen L, Versteeg R, Bernards R. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell. 2010;142(2):218–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  244. Jaboin J, Kim CJ, Kaplan DR, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3’-kinase pathway. Cancer Res. 2002;62(22):6756–63.

    CAS  PubMed  Google Scholar 

  245. Li Z, Jaboin J, Dennis PA, Thiele CJ. Genetic and pharmacologic identification of Akt as a mediator of brain-derived neurotrophic factor/TrkB rescue of neuroblastoma cells from chemotherapy-induced cell death. Cancer Res. 2005;65(6):2070–5.

    Article  CAS  PubMed  Google Scholar 

  246. Li Z, Zhang J, Liu Z, Woo CW, Thiele CJ. Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death. Cell Death Differ. 2007;14(2):318–26.

    Article  PubMed  CAS  Google Scholar 

  247. Li Z, Thiele CJ. Targeting Akt to increase the sensitivity of neuroblastoma to chemotherapy: lessons learned from the brain-derived neurotrophic factor/TrkB signal transduction pathway. Expert Opin Ther Targets. 2007;11(12):1611–21.

    Article  CAS  PubMed  Google Scholar 

  248. Opel D, Poremba C, Simon T, Debatin KM, Fulda S. Activation of Akt predicts poor outcome in neuroblastoma. Cancer Res. 2007;67(2):735–45.

    Article  CAS  PubMed  Google Scholar 

  249. Izycka-Swieszewska E, Drozynska E, Rzepko R, Kobierska-Gulida G, Grajkowska W, Perek D, Balcerska A. Analysis of PI3K/AKT/mTOR signalling pathway in high risk neuroblastic tumours. Pol J Pathol. 2010;61(4):192–8.

    PubMed  Google Scholar 

  250. Johnsen JI, Segerstrom L, Orrego A, Elfman L, Henriksson M, Kagedal B, Eksborg S, Sveinbjornsson B, Kogner P. Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo. Oncogene. 2008;27(20):2910–22.

    Article  CAS  PubMed  Google Scholar 

  251. Chanthery YH, Gustafson WC, Itsara M, Persson A, Hackett CS, Grimmer M, Charron E, Yakovenko S, Kim G, Matthay KK, Weiss WA. Paracrine signaling through MYCN enhances tumor-vascular interactions in neuroblastoma. Sci Transl Med. 2012;4(115):115ra113.

    Article  CAS  Google Scholar 

  252. Westhoff MA, Faham N, Marx D, Nonnenmacher L, Jennewein C, Enzenmuller S, Gonzalez P, Fulda S, Debatin KM. Sequential dosing in chemosensitization: targeting the PI3K/Akt/mTOR pathway in neuroblastoma. PLoS One. 2013;8(12):e83128.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  253. Bender A, Opel D, Naumann I, Kappler R, Friedman L, von Schweinitz D, Debatin KM, Fulda S. PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis. Oncogene. 2011;30(4):494–503.

    Article  CAS  PubMed  Google Scholar 

  254. Li Z, Tan F, Liewehr DJ, Steinberg SM, Thiele CJ. In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine. J Natl Cancer Inst. 2010;102(11):758–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Li Z, Oh DY, Nakamura K, Thiele CJ. Perifosine-induced inhibition of Akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo. Cancer. 2011;117(23):5412–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Li Z, Yan S, Attayan N, Ramalingam S, Thiele CJ. Combination of an allosteric Akt Inhibitor MK-2206 with etoposide or rapamycin enhances the antitumor growth effect in neuroblastoma. Clin Cancer Res. 2012;18(13):3603–15.

    Article  CAS  PubMed  Google Scholar 

  257. Houghton PJ, Morton CL, Kolb EA, Gorlick R, Lock R, Carol H, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA. Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008;50(4):799–805.

    Article  PubMed  Google Scholar 

  258. Kurmasheva RT, Harwood FC, Houghton PJ. Differential regulation of vascular endothelial growth factor by Akt and mammalian target of rapamycin inhibitors in cell lines derived from childhood solid tumors. Mol Cancer Ther. 2007;6(5):1620–8.

    Article  CAS  PubMed  Google Scholar 

  259. Zhang H, Dou J, Yu Y, Zhao Y, Fan Y, Cheng J, Xu X, Liu W, Guan S, Chen Z, Shi Y, Patel R, Vasudevan SA, Zage PE, Zhang H, Nuchtern JG. mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling. Apoptosis. 2015;20(1):50–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Geoerger B, Kieran MW, Grupp S, Perek D, Clancy J, Krygowski M, Ananthakrishnan R, Boni JP, Berkenblit A, Spunt SL. Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma. Eur J Cancer. 2012;48(2):253–62.

    Article  CAS  PubMed  Google Scholar 

  261. Yan S, Li Z, Thiele CJ. Inhibition of STAT3 with orally active JAK inhibitor, AZD1480, decreases tumor growth in Neuroblastoma and Pediatric Sarcomas In vitro and In vivo. Oncotarget. 2013;4(3):433–45.

    Article  PubMed  PubMed Central  Google Scholar 

  262. Hsu DM, Agarwal S, Benham A, Coarfa C, Trahan DN, Chen Z, Stowers PN, Courtney AN, Lakoma A, Barbieri E, Metelitsa LS, Gunaratne P, Kim ES, Shohet JM. G-CSF receptor positive neuroblastoma subpopulations are enriched in chemotherapy-resistant or relapsed tumors and are highly tumorigenic. Cancer Res. 2013;73(13):4134–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Agarwal S, Lakoma A, Chen Z, Hicks J, Metelitsa LS, Kim ES, Shohet JM. G-CSF promotes neuroblastoma tumorigenicity and metastasis via STAT3-dependent cancer stem cell activation. Cancer Res. 2015;75(12):2566–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Molenaar JJ, Koster J, Ebus ME, van Sluis P, Westerhout EM, de Preter K, Gisselsson D, Ora I, Speleman F, Caron HN, Versteeg R. Copy number defects of G1-cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis. Genes Chromosomes Cancer. 2012;51(1):10–9.

    Article  CAS  PubMed  Google Scholar 

  265. Molenaar JJ, Ebus ME, Koster J, van Sluis P, van Noesel CJ, Versteeg R, Caron HN. Cyclin D1 and CDK4 activity contribute to the undifferentiated phenotype in neuroblastoma. Cancer Res. 2008;68(8):2599–609.

    Article  CAS  PubMed  Google Scholar 

  266. Gogolin S, Ehemann V, Becker G, Brueckner LM, Dreidax D, Bannert S, Nolte I, Savelyeva L, Bell E, Westermann F. CDK4 inhibition restores G(1)-S arrest in MYCN-amplified neuroblastoma cells in the context of doxorubicin-induced DNA damage. Cell Cycle. 2013;12(7):1091–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013;19(22):6173–82.

    Article  CAS  PubMed  Google Scholar 

  268. Cole KA, Huggins J, Laquaglia M, Hulderman CE, Russell MR, Bosse K, Diskin SJ, Attiyeh EF, Sennett R, Norris G, Laudenslager M, Wood AC, Mayes PA, Jagannathan J, Winter C, Mosse YP, et al. RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma. Proc Natl Acad Sci U S A. 2011;108(8):3336–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Walton MI, Eve PD, Hayes A, Valenti MR, De Haven Brandon AK, Box G, Hallsworth A, Smith EL, Boxall KJ, Lainchbury M, Matthews TP, Jamin Y, Robinson SP, Aherne GW, Reader JC, Chesler L, et al. CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs. Clin Cancer Res. 2012;18(20):5650–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Fouladi M, Park JR, Stewart CF, Gilbertson RJ, Schaiquevich P, Sun J, Reid JM, Ames MM, Speights R, Ingle AM, Zwiebel J, Blaney SM, Adamson PC. Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children’s Oncology Group phase I consortium report. J Clin Oncol. 2010;28(22):3623–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Mueller S, Yang X, Sottero TL, Gragg A, Prasad G, Polley MY, Weiss WA, Matthay KK, Davidoff AM, DuBois SG, Haas-Kogan DA. Cooperation of the HDAC inhibitor vorinostat and radiation in metastatic neuroblastoma: efficacy and underlying mechanisms. Cancer Lett. 2011;306(2):223–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Witt O, Milde T, Deubzer HE, Oehme I, Witt R, Kulozik A, Eisenmenger A, Abel U, Karapanagiotou-Schenkel I. Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma or leukemia. Klin Padiatr. 2012;224(6):398–403.

    Article  CAS  PubMed  Google Scholar 

  273. Jaboin J, Wild J, Hamidi H, Khanna C, Kim CJ, Robey R, Bates SE, Thiele CJ. 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(21):6108–15.

    CAS  PubMed  Google Scholar 

  274. Yang Q, Zage P, Kagan D, Tian Y, Seshadri R, Salwen HR, Liu S, Chlenski A, Cohn SL. Association of epigenetic inactivation of RASSF1A with poor outcome in human neuroblastoma. Clin Cancer Res. 2004;10(24):8493–500.

    Article  CAS  PubMed  Google Scholar 

  275. Charlet J, Schnekenburger M, Brown KW, Diederich M. DNA demethylation increases sensitivity of neuroblastoma cells to chemotherapeutic drugs. Biochem Pharmacol. 2012;83(7):858–65.

    Article  CAS  PubMed  Google Scholar 

  276. George RE, Lahti JM, Adamson PC, Zhu K, Finkelstein D, Ingle AM, Reid JM, Krailo M, Neuberg D, Blaney SM, Diller L. Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: a Children’s Oncology Group study. Pediatr Blood Cancer. 2010;55(4):629–38.

    Article  PubMed  PubMed Central  Google Scholar 

  277. Krishnadas DK, Shusterman S, Bai F, Diller L, Sullivan JE, Cheerva AC, George RE, Lucas KG. A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma. Cancer Immunol Immunother. 2015;64(10):1251–60.

    Article  CAS  PubMed  Google Scholar 

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  1. National Cancer Institute, 10 Center Dr. MSC-1105, Building 10, CRC, Room 1W-3940, Bethesda, MD, 20892, USA

    Zhihui Liu & Carol J. Thiele

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  1. Zhihui Liu
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  1. Section on Medical Neuroendocrinology, Eunice Kennedy Shriver NICHD, NIH, Bethesda, Maryland, USA

    Karel Pacak

  2. Department of Nuclear Medicine, Aix-Marseille University, Marseille, France

    David Taïeb

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Liu, Z., Thiele, C.J. (2017). Molecular Genetics of Neuroblastoma. In: Pacak, K., Taïeb, D. (eds) Diagnostic and Therapeutic Nuclear Medicine for Neuroendocrine Tumors. Contemporary Endocrinology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-46038-3_5

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