International Journal of Clinical Oncology

, Volume 17, Issue 3, pp 190–195

Molecular and genetic bases of neuroblastoma

Review Article

Abstract

Neuroblastoma, which is derived from the sympathetic nervous system, is the second most common pediatric solid malignant tumor. This pediatric tumor has a heterogeneous course, ranging from spontaneous regression to inexorable progression and death, depending on the biological features of the tumor. Identification of risk groups on the basis of clinical and molecular prognostic variables has allowed tailor-made therapy to improve outcomes and minimize the risk of deleterious consequences of therapy. In Japan, current therapeutic stratification of patients with neuroblastoma is based on risk assessment according to combinations of age, tumor stage, MYCN status, DNA ploidy status, and histopathology; however, unfavorable neuroblastoma is still one of the most difficult tumors to cure, with only 40 % long-term survival despite intensive multimodal therapy. Further refined therapeutic stratification based on newly identified prognostic factors will be required to improve the outcome of patients with unfavorable neuroblastoma and reduce the side effects of therapies for patients with favorable neuroblastoma. In the present review, we describe recent topics on the molecular and genetic bases of neuroblastoma; we hope this review will be helpful for understanding the mechanism of neuroblastoma tumorigenesis and aggressiveness and for developing a new therapeutic stratification and new protocols for neuroblastoma treatments.

Keywords

Neuroblastoma Molecular and genetic abnormality 

References

  1. 1.
    Westermann F, Schwab M (2002) Genetic parameters of neuroblastomas. Cancer Lett 184:127–147PubMedCrossRefGoogle Scholar
  2. 2.
    Maris JM, Hogarty MD, Bagatell R et al (2007) Neuroblastoma. Lancet 369:2106–2120PubMedCrossRefGoogle Scholar
  3. 3.
    van Noesela MM, Versteeg R (2004) Pediatric neuroblastomas: genetic and epigenetic ‘danse macabre’. Gene 325:1–15Google Scholar
  4. 4.
    D’Angio GJ, Evans AE, Koop CE (1971) Special pattern of widespread neuroblastoma with a favourable prognosis. Lancet 297:1046–1049CrossRefGoogle Scholar
  5. 5.
    Kato GJ, Lee WM, Chen LL et al (1992) Max: functional domains and interaction with c-Myc. Genes Dev 6:81–92PubMedCrossRefGoogle Scholar
  6. 6.
    Zindy F, Eischen CM, Randle DH et al (1998) Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 12:2424–2433PubMedCrossRefGoogle Scholar
  7. 7.
    Kohl NE, Kanda N, Schreck RR et al (1983) Transposition and amplification of oncogene related sequence in human neuroblastomas. Cell 35:359–367PubMedCrossRefGoogle Scholar
  8. 8.
    Schwab M, Alitalo K, Klempnauer KH et al (1983) Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumor. Nature 305:245–248PubMedCrossRefGoogle Scholar
  9. 9.
    Corvi R, Amler LC, Savelyeva L et al (1994) MYCN is retained in single copy at chromosome 2 band p23–24 during amplification in human neuroblastoma cells. Proc Natl Acad Sci USA 91:5523–5527PubMedCrossRefGoogle Scholar
  10. 10.
    Schwab M (1998) Amplification of oncogenes in human cancer cells. Bioessays 20:473–479PubMedCrossRefGoogle Scholar
  11. 11.
    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
  12. 12.
    Brodeur G, Seeger RC, Schwab M et al (1984) Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224:1121–1124PubMedCrossRefGoogle Scholar
  13. 13.
    Rubie H, Hartmann O, Michon J et al (1997) Localized neuroblastoma: MYCN amplification is the main prognostic factor-results of the NBL 90 study. J Clin Oncol 15:1171–1182PubMedGoogle Scholar
  14. 14.
    Caron H (1995) Allelic loss of chromosome 1 and additional chromosome 17 material are both unfavourable prognostic markers in neuroblastoma. Med Pediatr Oncol 24:215–221PubMedCrossRefGoogle Scholar
  15. 15.
    Bown N, Cotterill S, Lastowska M et al (1999) Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 340:1954–1961PubMedCrossRefGoogle Scholar
  16. 16.
    Okabe-Kado J, Kasukabe T, Honma Y et al (2005) Clinical significance of serum NM23-H1 protein in neuroblastoma. Cancer Sci 96:653–660PubMedCrossRefGoogle Scholar
  17. 17.
    Adida C, Berrebi D, Peuchmaur M et al (1998) Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. Lancet 351:882–883PubMedCrossRefGoogle Scholar
  18. 18.
    White PS, Maris JM, Beltinger C et al (1995) A region of consistent deletion in neuroblastoma maps within 1p36.2-3. Proc Natl Acad Sci USA 92:5520–5524PubMedCrossRefGoogle Scholar
  19. 19.
    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 Chromosom Cancer 30:168–174PubMedCrossRefGoogle Scholar
  20. 20.
    Bauer A, Savelyeva L, Claas A et al (2001) Smallest region of overlapping deletion in 1p36 in human neuroblastoma: a 1 Mbp cosmid and PAC contig. Genes Chromosom Cancer 31:228–239PubMedCrossRefGoogle Scholar
  21. 21.
    Brodeur GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3:203–216PubMedCrossRefGoogle Scholar
  22. 22.
    Wei JS, Song YK, Durinck S et al (2008) The MYCN oncogene is a direct target of miR-34a. Oncogene 27:5204–5213PubMedCrossRefGoogle Scholar
  23. 23.
    Cole KA, Attiyeh EF, Mosse YP et al (2008) A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Mol Cancer Res 6:735–742PubMedCrossRefGoogle Scholar
  24. 24.
    Bagchi A, Papazoglu C, Wu Y et al (2007) CHD5 is a tumor suppressor at human 1p36. Cell 128:459–475PubMedCrossRefGoogle Scholar
  25. 25.
    Munirajan AK, Ando K, Mukai A et al (2008) KIF1Bbeta functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptotic cell death. J Biol Chem 283:24426–24434PubMedCrossRefGoogle Scholar
  26. 26.
    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
  27. 27.
    Spitz R, Hero B, Ernestus K et al (2003) Deletions in chromosome arms 3p and 11q are new prognostic markers in localized and 4s neuroblastoma. Clin Cancer Res 9:52–58PubMedGoogle Scholar
  28. 28.
    Attiyeh EF, London WB, Mosse YP et al (2005) Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353:2243–2253PubMedCrossRefGoogle Scholar
  29. 29.
    Cohn SL, Pearson AD, London WB et al (2009) The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 27:289–297PubMedCrossRefGoogle Scholar
  30. 30.
    Tomioka N, Oba S, Ohira M et al (2008) Novel risk stratification of patients with neuroblastoma by genomic signature which is independent of molecular signature. Oncogene 27:441–449PubMedCrossRefGoogle Scholar
  31. 31.
    Ando K, Ohira M, Ozaki T et al (2008) Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation. Int J Cancer 123:2087–2094PubMedCrossRefGoogle Scholar
  32. 32.
    Ochiai H, Takenobu H, Nakagawa A et al (2010) Bmi1 is a MYCN target gene and regulates tumorigenesis via repression of KIF1Bβ and TSLC1 in neuroblastoma. Oncogene 29:2681–2690PubMedCrossRefGoogle Scholar
  33. 33.
    Kogner P, Barbany G, Dominici C et al (1993) Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis. Cancer Res 53:2044–2050PubMedGoogle Scholar
  34. 34.
    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
  35. 35.
    Nakagawara A, Azar CG, Scavarda NJ et al (1994) Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol 14:759–767PubMedGoogle Scholar
  36. 36.
    Eggert A, Grotzer MA, Zuzak TJ et al (2001) Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Cancer Res 61:1314–1319PubMedGoogle Scholar
  37. 37.
    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
  38. 38.
    Ejeskar K, Aburatani H, Abrahamsson J et al (1998) Loss of heterozygosity of 3p markers in neuroblastoma tumours implicate a tumour-suppressor locus distal to the FHIT gene. Br J Cancer 77:1787–1791PubMedCrossRefGoogle Scholar
  39. 39.
    Astuti D, Agathanggelou A, Honorio S et al (2001) RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours. Oncogene 20:7573–7577PubMedCrossRefGoogle Scholar
  40. 40.
    Mosse YP, Laudenslager M, Khazi D et al (2004) Germline PHOX2B mutation in hereditary neuroblastoma. Am J Hum Genet 75:727–730PubMedCrossRefGoogle Scholar
  41. 41.
    Trochet D, Bourdeaut F, Janoueix-Lerosey I et al (2004) Germ-line mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Am J Hum Genet 74:761–764PubMedCrossRefGoogle Scholar
  42. 42.
    Mossé YP, Laudenslager M, Longo L et al (2008) Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455:930–935PubMedCrossRefGoogle Scholar
  43. 43.
    Janoueix-Lerosey I, Lequin D, Brugières L et al (2008) Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455:967–970PubMedCrossRefGoogle Scholar
  44. 44.
    George RE, Sanda T, Hanna M et al (2008) Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 455:975–978PubMedCrossRefGoogle Scholar
  45. 45.
    Chen Y, Takita J, Choi YL et al (2008) Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455:971–974PubMedCrossRefGoogle Scholar
  46. 46.
    Look AT, Hayes FA, Shuster JJ et al (1991) Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9:581–591PubMedGoogle Scholar
  47. 47.
    Walton JD, Kattan DR, Thomas SK et al (2004) Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia 6:645–838CrossRefGoogle Scholar
  48. 48.
    Hansford LM, McKee AE, Zhang L et al (2007) Neuroblastoma cells isolated from bone marrow metastases contain a naturally enriched tumor-initiating cell. Cancer Res 67:11234–11243PubMedCrossRefGoogle Scholar
  49. 49.
    Smith KM, Datti A, Fujitani M et al (2010) Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens. EMBO Mol Med 2:371–384PubMedCrossRefGoogle Scholar
  50. 50.
    Grinshtein N, Datti A, Fujitani M et al (2011) Small molecule kinase inhibitor screen identifies polo-like kinase 1 as a target for neuroblastoma tumor-initiating cells. Cancer Res 71:1385–1395PubMedCrossRefGoogle Scholar
  51. 51.
    Corbeil D, Fargeas CA, Huttner WB (2001) Rat prominin, like its mouse and human orthologues, is a pentaspan membrane glycoprotein. Biochem Biophys Res Commun 285:939–944PubMedCrossRefGoogle Scholar
  52. 52.
    O’Brien CA, Kreso A, Jamieson CHM (2010) Cancer stem cells and self-renewal. Clin Cancer Res 16:3113–3120PubMedCrossRefGoogle Scholar
  53. 53.
    Takenobu H, Shimozato O, Nakamura T et al (2011) CD133 suppresses neuroblastoma cell differentiation via signal pathway modification. Oncogene 30:97–105PubMedCrossRefGoogle Scholar
  54. 54.
    Mahller YY, Williams JP, Baird WH et al (2009) Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus. PLoS ONE 4:e4235PubMedCrossRefGoogle Scholar
  55. 55.
    Shmelkov SV, Jun L, St Clair R et al (2004) Alternative promoters regulate transcription of the gene that encodes stem cell surface protein AC133. Blood 103:2055–2061PubMedCrossRefGoogle Scholar
  56. 56.
    Schiapparelli P, Enguita-Germán M, Balbuena J et al (2010) Analysis of stemness gene expression and CD133 abnormal methylation in neuroblastoma cell lines. Oncol Rep 24:1355–1362PubMedGoogle Scholar
  57. 57.
    Baba T, Convery PA, Matsumura N et al (2009) Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 28:209–218PubMedCrossRefGoogle Scholar
  58. 58.
    Yi JM, Tsai HC, Glöckner SC et al (2008) Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Res 68:8094–8103PubMedCrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2012

Authors and Affiliations

  1. 1.Division of Biochemistry and Molecular CarcinogenesisChiba Cancer Center Research InstituteChibaJapan
  2. 2.Division of Biochemistry and Innovative Cancer TherapeuticsChiba Cancer Center Research InstituteChibaJapan

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