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.
Similar content being viewed by others
References
Westermann F, Schwab M (2002) Genetic parameters of neuroblastomas. Cancer Lett 184:127–147
Maris JM, Hogarty MD, Bagatell R et al (2007) Neuroblastoma. Lancet 369:2106–2120
van Noesela MM, Versteeg R (2004) Pediatric neuroblastomas: genetic and epigenetic ‘danse macabre’. Gene 325:1–15
D’Angio GJ, Evans AE, Koop CE (1971) Special pattern of widespread neuroblastoma with a favourable prognosis. Lancet 297:1046–1049
Kato GJ, Lee WM, Chen LL et al (1992) Max: functional domains and interaction with c-Myc. Genes Dev 6:81–92
Zindy F, Eischen CM, Randle DH et al (1998) Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 12:2424–2433
Kohl NE, Kanda N, Schreck RR et al (1983) Transposition and amplification of oncogene related sequence in human neuroblastomas. Cell 35:359–367
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 305:245–248
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 91:5523–5527
Schwab M (1998) Amplification of oncogenes in human cancer cells. Bioessays 20:473–479
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 313:1111–1116
Brodeur G, Seeger RC, Schwab M et al (1984) Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224:1121–1124
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 15:1171–1182
Caron H (1995) Allelic loss of chromosome 1 and additional chromosome 17 material are both unfavourable prognostic markers in neuroblastoma. Med Pediatr Oncol 24:215–221
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 340:1954–1961
Okabe-Kado J, Kasukabe T, Honma Y et al (2005) Clinical significance of serum NM23-H1 protein in neuroblastoma. Cancer Sci 96:653–660
Adida C, Berrebi D, Peuchmaur M et al (1998) Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. Lancet 351:882–883
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 92:5520–5524
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 30:168–174
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 31:228–239
Brodeur GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3:203–216
Wei JS, Song YK, Durinck S et al (2008) The MYCN oncogene is a direct target of miR-34a. Oncogene 27:5204–5213
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 6:735–742
Bagchi A, Papazoglu C, Wu Y et al (2007) CHD5 is a tumor suppressor at human 1p36. Cell 128:459–475
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 283:24426–24434
Guo C, White PS, Weiss MJ et al (1999) Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Oncogene 18:4948–4957
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 9:52–58
Attiyeh EF, London WB, Mosse YP et al (2005) Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353:2243–2253
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 27:289–297
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 27:441–449
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 123:2087–2094
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 29:2681–2690
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 53:2044–2050
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 328:847–854
Nakagawara A, Azar CG, Scavarda NJ et al (1994) Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol 14:759–767
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 61:1314–1319
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 6:529–535
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 77:1787–1791
Astuti D, Agathanggelou A, Honorio S et al (2001) RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours. Oncogene 20:7573–7577
Mosse YP, Laudenslager M, Khazi D et al (2004) Germline PHOX2B mutation in hereditary neuroblastoma. Am J Hum Genet 75:727–730
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 74:761–764
Mossé YP, Laudenslager M, Longo L et al (2008) Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455:930–935
Janoueix-Lerosey I, Lequin D, Brugières L et al (2008) Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455:967–970
George RE, Sanda T, Hanna M et al (2008) Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 455:975–978
Chen Y, Takita J, Choi YL et al (2008) Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455:971–974
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 9:581–591
Walton JD, Kattan DR, Thomas SK et al (2004) Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia 6:645–838
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 67:11234–11243
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 2:371–384
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 71:1385–1395
Corbeil D, Fargeas CA, Huttner WB (2001) Rat prominin, like its mouse and human orthologues, is a pentaspan membrane glycoprotein. Biochem Biophys Res Commun 285:939–944
O’Brien CA, Kreso A, Jamieson CHM (2010) Cancer stem cells and self-renewal. Clin Cancer Res 16:3113–3120
Takenobu H, Shimozato O, Nakamura T et al (2011) CD133 suppresses neuroblastoma cell differentiation via signal pathway modification. Oncogene 30:97–105
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:e4235
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 103:2055–2061
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 24:1355–1362
Baba T, Convery PA, Matsumura N et al (2009) Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 28:209–218
Yi JM, Tsai HC, Glöckner SC et al (2008) Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Res 68:8094–8103
Acknowledgments
We thank Mr. Daniel Mrozek, Medical English Service, for editorial assistance. This work was supported in part by a Grant-in-Aid from the National Cancer Center Research and Development Fund of Japan (4), a Grant-in-Aid from the Ministry of Health, Labor, and Welfare of Japan for Third Term Comprehensive Control Research for Cancer, a Grant-in-Aid for Scientific Research (B) (24390269), and a Grant-in-Aid from the Uehara Memorial Foundation.
Conflict of interest
We have no financial relationships to disclose.
Author information
Authors and Affiliations
Corresponding authors
About this article
Cite this article
Kamijo, T., Nakagawara, A. Molecular and genetic bases of neuroblastoma. Int J Clin Oncol 17, 190–195 (2012). https://doi.org/10.1007/s10147-012-0415-7
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10147-012-0415-7