Clinical and Translational Oncology

, Volume 9, Issue 8, pp 478–483 | Cite as

Molecular biology of neuroblastoma

  • V. CastelEmail author
  • E. Grau
  • R. Noguera
  • F. Martínez
Educational Series


Neuroblastoma is one of the most frequently occurring solid tumours in children, especially in the first year of life, when it accounts for 50% of all tumours. It is the second most common cause of death in children, only preceded by accidents. The most peculiar characteristic of neuroblastoma is its clinical heterogeneity. Approximately half of the cases are classified as high risk, with overall survival rates around 40% despite intensive multimodal therapy. Nevertheless, other subsets of neuroblastomas will undergo spontaneous regression and others will show very slow progression. Despite many advances in the past three decades, neuroblastoma has remained an enigmatic challenge to clinical and basic scientists. Elucidation of the exact molecular pathways of neuroblastoma will enable researchers and clinicians to stratify the disease and adapt therapy to the risk of relapse or progression. This review focuses on recent advances in our understanding of the biology of this complex paediatric tumour. Neuroblastoma is already one of the first examples for the use of tumoral genetic markers as a tool for defining tumour behaviour and to aid clinical staging.

Key words

Neuroblastoma MYCN del 1p Embryonal tumours Molecular biology Pangenomic studies Paediatric cancer 


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  1. 1.
    Castel V, Cañete A (2005) Tumores de la Cresta Neural. In: Madero L, Muñoz A (eds) Hematologia y Oncologia Pediatrica, 2nd Edn. Ergon, Madrid, pp 571–578Google Scholar
  2. 2.
    Brodeur GM, Maris JM (2006) Neuroblastoma. In: Pizzo PA, Poplack DG (eds) Principles and practice of pediatric oncology, 5th Edn. J.B. Lippincott Company, Philadelphia, pp 933–970Google Scholar
  3. 3.
    Schwab M, Westermann F, Hero B, Berthold F (2003) Neuroblastoma: biology and molecular and chromosomal pathology. Lancet Oncol 4: 472–480PubMedCrossRefGoogle Scholar
  4. 4.
    Brodeur GM, Pritchard J, Berthold F et al (1993) Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11:1466–1477PubMedGoogle Scholar
  5. 5.
    Cecchetto G, Mosseri V, De Bernardi B et al (2005) Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 23:8483–8489PubMedCrossRefGoogle Scholar
  6. 6.
    Shimada H, Chatten J, Newton WA et al (1984) Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst 73:405–416PubMedGoogle Scholar
  7. 7.
    Shimada H, Ambros IM, Dehner LP et al (1999) Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Cancer 86:349–363PubMedCrossRefGoogle Scholar
  8. 8.
    Seeger RC, Brodeur GM, Sather H et al (1985) Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 313:1111–1116PubMedCrossRefGoogle Scholar
  9. 9.
    Katzenstein HM, Bowman LC, Brodeur GM et al (1998) Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience — a pediatric oncology group study. J Clin Oncol 16:2007–2017PubMedGoogle Scholar
  10. 10.
    Cohn SL, Tweddle DA (2004) MYCN amplification remains prognostically strong 20 years after its “clinical debut”. Eur J Cancer 40:2639–2642PubMedCrossRefGoogle Scholar
  11. 11.
    Amler LC, Schwab M (1989) Amplified N-myc in human neuroblastoma cells is often arranged as clustered tandem repeats of differently recombined DNA. Mol Cell Biol 9:4903–4913PubMedGoogle Scholar
  12. 12.
    Reiter JL, Brodeur GM (1998) MYCN is the only highly expressed gene from the core amplified domain in human neuroblastomas. Genes Chromosomes Cancer 23:134–140PubMedCrossRefGoogle Scholar
  13. 13.
    Chan HS, Gallie BL, DeBoer G et al (1997) MYCN protein expression as a predictor of neuroblastoma prognosis. Clin Cancer Res 3:1699–1706PubMedGoogle Scholar
  14. 14.
    Cohn SL, London WB, Huang D et al (2000) MYCN expression is not prognostic of adverse outcome in advanced-stage neuroblastoma with nonamplified MYCN. J Clin Oncol 18:3604–3613PubMedGoogle Scholar
  15. 15.
    Ambros IM, Benard J, Boavida M et al (2003) Quality assessment of genetic markers used for therapy stratification. J Clin Oncol 21:2077–2084PubMedCrossRefGoogle Scholar
  16. 16.
    Spitz R, Hero B, Skowron M et al (2004) MYCN-status in neuroblastoma: characteristics of tumours showing amplification, gain, and non-amplification. Eur J Cancer 40:2753–2759PubMedCrossRefGoogle Scholar
  17. 17.
    Noguera R, Cañete A, Pellín A et al (2003) MYCN gain and MYCN amplification in a stage 4S neuroblastoma. Cancer Genet Cytogenet 140:157–161PubMedCrossRefGoogle Scholar
  18. 18.
    Valent A, Le Roux G, Barrois M et al (2002) MYCN gene overrepresentation detected in primary neuroblastoma tumour cells without amplification. J Pathol 198:495–501PubMedCrossRefGoogle Scholar
  19. 19.
    Squire JA, Thorner P, Marrano P et al (1996) Identification of MYCN copy number heterogeneity by direct FISH analysis of neuroblastoma preparations. Mol Diagn 1:281–289PubMedCrossRefGoogle Scholar
  20. 20.
    Caron H, van Sluis P, van Roy N et al (1994) 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 55:341–347PubMedGoogle Scholar
  21. 21.
    Lastowska M, Cotterill S, Pearson AD et al (1997) Gain of chromosome arm 17q predicts unfavourable outcome in neuroblastoma patients. U.K. Children’s Cancer Study Group and the U.K. Cancer Cytogenetics Group. Eur J Cancer 33:1627–1633PubMedCrossRefGoogle Scholar
  22. 22.
    Vandesompele J, Baudis M, De Preter K et al (2005) Unequivocal delineation of clinicogenetic subgroups and development of a new model for improved outcome prediction in neuroblastoma. J Clin Oncol 23:2280–2299PubMedCrossRefGoogle Scholar
  23. 23.
    Caron H, van Sluis P, de Kraker J et al (1996) Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med 334:225–230PubMedCrossRefGoogle Scholar
  24. 24.
    Maris JM, Weiss MJ, Guo C et al (2000) Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblastoma patients: a Children’s Cancer Group study. J Clin Oncol 18:1888–1899PubMedGoogle Scholar
  25. 25.
    Spitz R, Hero B, Westermann F et al (2002) Fluorescence in situ hybridization analyses of chromosome band 1p36 in neuroblastoma detect two classes of alterations. Genes Chromosomes Cancer 34:299–305PubMedCrossRefGoogle Scholar
  26. 26.
    Rubie H, Delattre O, Hartmann O et al (1997) Loss of chromosome 1p may have a prognostic value in localised neuroblastoma: results of the French NBL 90 Study. Neuroblastoma Study Group of the Société Française d’Oncologie Pédiatrique (SFOP). Eur J Cancer 33:1917–1922PubMedCrossRefGoogle Scholar
  27. 27.
    Caron H, Spieker N, Godfried M et al (2001) Chromosome bands 1p35-36 contain two distinct neuroblastoma tumor suppressor loci, one of which is imprinted. Genes Chromosomes Cancer 30:168–174PubMedCrossRefGoogle Scholar
  28. 28.
    Spitz R, Hero B, Ernestus K, Berthold F (2003) FISH analyses for alterations in chromosomes 1, 2, 3, and 11 define high-risk groups in neuroblastoma. Med Pediatr Oncol 41:30–35PubMedCrossRefGoogle Scholar
  29. 29.
    Guo C, White PS, Weiss MJ et al (1999) Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Oncogene 18:4948–4957PubMedCrossRefGoogle Scholar
  30. 30.
    Attiyeh EF, London WB, Mossé YP et al; Children’s Oncology Group (2005) Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353:2243–2253PubMedCrossRefGoogle Scholar
  31. 31.
    Bowman LC, Castleberry RP, Cantor A et al (1997) Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. J Natl Cancer Inst 89:373–380PubMedCrossRefGoogle Scholar
  32. 32.
    Brodeur GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3:203–216PubMedCrossRefGoogle Scholar
  33. 33.
    Maris JM, Weiss MJ, Mosse Y et al (2002) Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13. Cancer Res 62:6651–6658PubMedGoogle Scholar
  34. 34.
    Weese-Mayer DE, Berry-Kravis EM, Zhou L et al (2003) 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 123:267–278PubMedCrossRefGoogle Scholar
  35. 35.
    Mosse YP, Laudenslager M, Khazi D et al (2004) Germline PHOX2B mutation in hereditary neuroblastoma. Am J Hum Genet 75:727–730PubMedCrossRefGoogle Scholar
  36. 36.
    Nakagawara A (2001) Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 169:107–114PubMedCrossRefGoogle Scholar
  37. 37.
    Nakagawara A, Arima-Nakagawara M, Scavarda NJ et al (1993) Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 328:847–854PubMedCrossRefGoogle Scholar
  38. 38.
    Tanaka T, Hiyama E, Sugimoto T et al (1995) trk A gene expression in neuroblastoma. The clinical significance of an immunohistochemical study. Cancer 76:1086–1095PubMedCrossRefGoogle Scholar
  39. 39.
    Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM (1994) Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol 14:759–767PubMedGoogle Scholar
  40. 40.
    Keshelava N, Zuo JJ, Chen P et al (2001) Loss of p53 function confers high-level multidrug resistance in neuroblastoma cell lines. Cancer Res 61:6185–6193PubMedGoogle Scholar
  41. 41.
    Carr J, Bell E, Pearson AD et al (2006) Increased frequency of aberrations in the p53/MDM2/p14(ARF) pathway in neuroblastoma cell lines established at relapse. Cancer Res 66:2138–2145PubMedCrossRefGoogle Scholar
  42. 42.
    Yaari S, Jacob-Hirsch J, Amariglio N et al (2005) Disruption of cooperation between Ras and MycN in human neuroblastoma cells promotes growth arrest. Clin Cancer Res 11:4321–4330PubMedCrossRefGoogle Scholar
  43. 43.
    Cohn SL, London WB, Huang D et al (2000) MYCN expression is not prognostic of adverse outcome in advanced-stage neuroblastoma with nonamplified MYCN. J Clin Oncol 18:3604–3613PubMedGoogle Scholar
  44. 44.
    Tang XX, Zhao H, Kung B et al (2006) The MYCN enigma: significance of MYCN expression in neuroblastoma. Cancer Res 66:2826–2833PubMedCrossRefGoogle Scholar
  45. 45.
    Haber M, Smith J, Bordow SB et al (2006) Association of high-level MRP1 expression with poor clinical outcome in a large prospective study of primary neuroblastoma. J Clin Oncol 24: 1546–1553PubMedCrossRefGoogle Scholar
  46. 46.
    de Cremoux P, Jourdan-Da-Silva N, Couturier J et al (2007) Role of chemotherapy resistance genes in outcome of neuroblastoma. Pediatr Blood Cancer 48:311–317PubMedCrossRefGoogle Scholar
  47. 47.
    Fulda S, Debatin KM (2003) Apoptosis pathways in neuroblastoma therapy. Cancer Lett 197: 131–135PubMedCrossRefGoogle Scholar
  48. 48.
    Pritchard J, Hickman JA (1994) Why does stage 4s neuroblastoma regress spontaneously? Lancet 344:869–870PubMedCrossRefGoogle Scholar
  49. 49.
    Teitz T, Wei T, Valentine MB et al (2000) Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 6:529–535PubMedCrossRefGoogle Scholar
  50. 50.
    Romero ME, Fulton BK, Davis MM (2001) Caspase 8 expression in tumors specimens from 71 neuroblastoma patients. Proc Am Assoc Cancer Res 42:1635Google Scholar
  51. 51.
    Fulda S, Poremba C, Berwanger B et al (2006) Loss of caspase-8 expression does not correlate with MYCN amplification, aggressive disease, or prognosis in neuroblastoma. Cancer Res 66:10016–10023PubMedCrossRefGoogle Scholar
  52. 52.
    Goldsmith KC, Hogarty MD (2005) Targeting programmed cell death pathways with experimental therapeutics: opportunities in high-risk neuroblastoma. Cancer Lett 228(1–2):133–141PubMedCrossRefGoogle Scholar
  53. 53.
    Schouten JP, McElgunn CJ, Waaijer R et al (2002). Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e57.PubMedCrossRefGoogle Scholar
  54. 54.
    Bruno DL, Burgess T, Ren H et al (2006). High-throughput analysis of chromosome abnormality in spontaneous miscarriage using an MLPA subtelomere assay with an ancillary FISH test for polyploidy. Am J Med Genet 140:2786–2793.CrossRefPubMedGoogle Scholar
  55. 55.
    Mosse YP, Greshock J, Weber BL, Maris JM (2005) Measurement and relevance of neuroblastoma DNA copy number changes in the postgenome era. Cancer Lett 228:83–90PubMedCrossRefGoogle Scholar
  56. 56.
    Wang Q, Diskin S, Rappaport E et al (2006) Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number. Cancer Res 66:6050–6062PubMedCrossRefGoogle Scholar
  57. 57.
    Mosse YP, Greshock J, Margolin A et al (2005) High-resolution detection and mapping of genomic DNA alterations in neuroblastoma. Genes Chromosomes Cancer 43:390–403PubMedCrossRefGoogle Scholar
  58. 58.
    Vandesompele J, Speleman F, Van Roy N et al (2001) Multicentre analysis of patterns of DNA gains and losses in 204 neuroblastoma tumors: how many genetic subgroups are there? Med Pediatr Oncol 36:5–10PubMedCrossRefGoogle Scholar
  59. 59.
    Schramm A, Schulte JH, Klein-Hitpass L et al (2005) Prediction of clinical outcome and biological characterization of neuroblastoma by expression profiling. Oncogene 24:7902–7912PubMedCrossRefGoogle Scholar
  60. 60.
    Schleiermacher G, Michon J, Huon I et al (2007) Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification. Br J Cancer 97:238–246PubMedCrossRefGoogle Scholar
  61. 61.
    Spitz R, Oberthuer A, Zapatka M et al (2006) Oligonucleotide array-based comparative genomic hybridization (aCGH) of 90 neuroblastomas reveals aberration patterns closely associated with relapse pattern and outcome. Genes Chromosomes Cancer 45:1130–1142PubMedCrossRefGoogle Scholar
  62. 62.
    Janoueix-Lerosey I, Hupé P, Maciorowski Z et al (2005) Preferential occurrence of chromosome breakpoints within early replicating regions in neuroblastoma. Cell Cycle 4:1842–1846PubMedGoogle Scholar
  63. 63.
    Schleiermacher G, Bourdeaut F, Combaret V et al (2005) Stepwise occurrence of a complex unbalanced translocation in neuroblastoma leading to insertion of a telomere sequence and late chromosome 17q gain. Oncogene 24:3377–3384PubMedCrossRefGoogle Scholar
  64. 64.
    Lastowska M, Viprey V, Santibanez-Koref M et al (2007) Identification of candidate genes involved in neuroblastoma progression by combining genomic and expression microarrays with survival data. Oncogene. Advance online publication 28 May. doi: 10.1038/sj.onc.1210552Google Scholar

Copyright information

© Feseo 2007

Authors and Affiliations

  1. 1.Unidad de Oncología PediátricaHospital Universitario La FeValenciaSpain
  2. 2.Department of Pathology. Medical SchoolUniversity of ValenciaValenciaSpain
  3. 3.Servicio de Genética y Diagnóstico PrenatalHospital Universitario La FeValenciaSpain

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