Association of Multiple Copies of the N-mycOncogene with Rapid Progression of Neuroblastomas

Abstract

Eighty-nine patients with untreated primary neuroblastomas were studied to determine the relation between the number of copies of the N-myc oncogene and survival without disease progression. Genomic amplification (3 to 300 copies) of N-myc was detected in 2 of 16 tumors in Stage II, 13 of 20 in Stage III, and 19 of 40 in Stage IV; in contrast, 8 Stage I and 5 Stage IV-S tumors all had 1 copy of the gene (P less than 0.01). Analysis of progression-free survival in all patients revealed that amplification of N-myc was associated with the worst prognosis (P less than 0.0001); the estimated progression-free survival at 18 months was 70 per cent, 30 per cent, and 5 per cent for patients whose tumors had 1, 3 to 10, or more than 10 N-myc copies, respectively. Of 16 Stage II tumors, 2 with amplification metastasized, whereas only 1 of 14 without amplification did so (P = 0.03). Stage IV tumors with amplification progressed most rapidly: nine months after diagnosis the estimated progression-free survival was 61 per cent, 47 per cent, and 0 per cent in patients whose tumors had 1, 3 to 10, or more than 10 copies, respectively (P less than 0.0001). These results suggest that genomic amplification of N-myc may have a key role in determining the aggressiveness of neuroblastomas.

Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma

“…We first showed that expression of NMyc, c-Met, TrkB, Ras and IL-8 levels were decreased, and EPHB6 and BLU levels increased, in AS-MIF transfectants. It has been shown that N-myc amplification is associated with advanced disease stage, rapid tumor progression and poor prognosis in neuroblastoma (Seeger et al, 1988(Seeger et al, , 1985. N-myc is associated with tumorigenesis and cell proliferation (Chambery et al, 1999).…”

Cell lines from MYCN transgenic murine tumours reflect the molecular and biological characteristics of human neuroblastoma

“…The present findings, however, demonstrating reduced tumourigenicity of the cell lines derived from mice hemizygous for the MYCN transgene, are in fact entirely consistent with our previous observations of spontaneous tumour formation in MYCN transgenic mice, where MYCN hemizygous mice were found to have both decreased tumour incidence and increased tumour latency by comparison with homozygous mice. [2][3][4] The results suggest the existence of intrinsic biological differences between tumour cells arising from mice either homozygous or hemizygous for the transgene and warrant further investigation.…”

“…3 Amplification of MYCN is a strong prognostic indicator of poor clinical outcome and is associated with advanced-stage disease, rapid tumour progression and a survival rate of less than 15%. 2,3 A murine model of neuroblastoma, established by targeted expression of the human MYCN oncogene in neuroectodermal cells of transgenic mice, has provided definitive evidence for the role of MYCN in neuroblastoma tumourigenesis. 4 This model closely mirrors human neuroblastoma with respect to location, histology, expression of neuronal markers and syntenic chromosomal alterations in murine tumours.…”

Expression of MYCN in pediatric synovial sarcoma

“…Amplification of the MYCN gene is associated with advanced tumor stage, tumor progression and poor outcome in neuroblastomas. 17 Several downstream targets of MYCN have been described and include the genes encoding the multidrug resistance protein 1 (MRP1), 18 the minichromosome maintenance protein 7 (MCM7), 19 the inhibitor of DNA binding protein 2 (ID2) 20 and the intermediate filament nestin. 21 Amplification and overexpression of MYCN has been described in tumors other than neuroblastoma, including alveolar rhabdomyosarcoma, 22 astrocytoma, 23 medulloblastoma, 24 retinoblastoma, 25 Wilms tumor 26 and breast carcinoma.…”