MYCN Expression Is Not Prognostic of Adverse Outcome in Advanced-Stage Neuroblastoma With Nonamplified MYCN

Cohn, Susan L.; London, Wendy B.; Huang, Dennis; Katzenstein, Howard M.; Salwen, Helen R.; Reinhart, Todd A.; Madafiglio, Janice; Marshall, Glenn M.; Norris, Murray D.; Haber, Michelle

doi:10.1200/jco.2000.18.21.3604

Cited by 96 publications

(77 citation statements)

References 44 publications

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“…Similarly, MYC overexpression without amplification has also been linked to a more favorable prognosis in patients with breast (36) and colorectal cancers (37). Better outcomes of patients with tumors that overexpress MYC or MYCN are due to either increased apoptosis or enhanced drug-sensitivity evoked by higher proliferation (35). Clinical observation has also been confirmed in in vitro experiments.…”

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confidence: 50%

“…Overexpressed genes encoding tyrosine kinase receptors (TrkA and EPHB6) and cell surface molecules (CD44, EFNB2, and EFNB3) have been described as favorable markers (13), but the significance of MYCN expression remains controversial since the survival of children suffering from NBL does not correlate with its expression (13,34,35). A high expression of MYCN in NBL cells may be associated with both a favorable (cells without MYCN amplification) and adverse prognosis (cells with amplified MYCN) (12).…”

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confidence: 99%

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Changes in MYCN expression in human neuroblastoma cell lines following cisplatin treatment may not be related to MYCN copy numbers

et al. 2013

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Abstract. Neuroblastoma is a tumor accounting for approximately 10% of all childhood malignancies and 50% of all childhood cancer-related deaths. MYCN gene copy number variation represents the most important prognostic factor in neuroblastoma. Prognostic significance of MYCN gene expression is more complicated and may depend on other factors such as MYCN gene copy number status. In the present study, we assessed MYCN gene expression using real-time RT-PCR following cisplatin treatment in three human neuroblastoma cell lines (UKF-NB-3, UKF-NB-4 and SK-N-AS) and their cisplatin-resistant counterparts. We also examined MYCN gene status and copy number (gain and amplification) variations using interphase and metaphase fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA). Only cisplatin-sensitive UKF-NB-4 cells exhibited decreased MYCN expression following treatment with cisplatin. Other sensitive neuroblastoma cells did not exhibit a change in MYCN expression. In contrast, cisplatin-resistant UKF-NB-4 and SK-N-AS cells exhibited increased MYCN expression irrespective of the number of MYCN copies or concentration of cisplatin in the medium. In MYCN-amplified neuroblastoma cells we did not observe any significant change in the number of MYCN copies after cisplatin treatment, whereas MYCN-non-amplified SK-N-AS cells revealed during cisplatin treatment an increased number of MYCN gene copies caused by 2p gain in the majority of cells by FISH. We postulated that cisplatin treatment does not result directly in altered transcription of MYCN. A functional change in MYCN mRNA levels and increased MYCN expression in cisplatin-resistant neuroblastoma cells do not have a clear relationship to MYCN copy numbers. These findings may further contribute to the understanding of cisplatin chemotherapy in connection with MYCN expression, and the possible copy number variations in MYCN neuroblastoma cells may be of importance since targeting of MYCN is being tested as neuroblastoma therapy.

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confidence: 99%

Changes in MYCN expression in human neuroblastoma cell lines following cisplatin treatment may not be related to MYCN copy numbers

et al. 2013

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“…Even though amplification of the MYCN oncogene has strong clinical impact (5), high levels of MYCN mRNA or protein in neuroblastoma only seems to correlate to poor outcome in specific patient subsets (17)(18)(19)(20). The molecular basis for these counterintuitive results is at present unclear.…”

Section: Discussionmentioning

confidence: 87%

High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma

Fredlund

Ringnér

Maris

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

152

158

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The childhood cancer neuroblastoma arises in the developing sympathetic nervous system and is a genotypically and phenotypically heterogeneous disease. Prognostic markers of poor survival probability include amplification of the MYCN oncogene and an undifferentiated morphology. Whereas these features discriminate high-from low-risk patients with precision, identification of poor outcome low-and intermediate-risk patients is more challenging. In this study, we analyze two large neuroblastoma microarray datasets using a priori-defined gene expression signatures. We show that differential overexpression of Myc transcriptional targets and low expression of genes involved in sympathetic neuronal differentiation predicts relapse and death from disease. This was evident not only for high-risk patients but was also robust in identifying groups of poor prognosis patients who were otherwise judged to be at low-or intermediate-risk for adverse outcome. These data suggest that pathway-specific gene expression profiling might be useful in the clinic to adjust treatment strategies for children with neuroblastoma.neuroblastoma ͉ pathway analysis ͉ MYCN ͉ Myc ͉ differentiation

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“…The RNA (25 ng) was subjected to real-time RT-PCR analyses using the TaqMan PCR reagent kit (Applied Biosystems, Foster City, CA) in a total volume of 50 l. Reverse transcription reaction was performed as follows: 30 min at 48°C, 15 min at 95°C, and then 40 cycles of PCR were done with DNA denaturation for 15 s at 95°C and primer annealing and extension for 1 min at 58°C. The gene-specific primers and probes for the MYCN target gene sequence and ␤ 2 -microglobulin endogenous control gene for use in real-time RT-PCR have been described previously (7). Quantitation of the sample was based on the cycle when the amplicon was first detected.…”

Section: Methodsmentioning

confidence: 99%

HuD, a Neuronal-specific RNA-binding Protein, Increases thein Vivo Stability of MYCN RNA

Manohar¹,

Short²,

Nguyen³

et al. 2002

Journal of Biological Chemistry

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MYCN amplification and consequent deregulated expression plays a crucial role in determining the clinical behavior of neuroblastoma. Enhanced expression of MYCN confers growth potential to neuroblastoma cells, and a direct link between MYCN expression and the development of neuroblastoma has been demonstrated in transgenic mice studies. Although the molecular pathways underlying the regulation of MYCN have not been fully elucidated, post-transcriptional mechanisms appear to be important. Previously, we reported that an embryonic lethal abnormal vision-like (ELAV) protein binds with high specificity to at least two AU-rich elements within the MYCN 3-untranslated region. In this study, we characterized the ability of cis-acting elements within the MYCN 3-untranslated region to destabilize mRNA in cells and examined the functional consequences of its interactions with the ELAV protein HuD. We show that at least 4 cis-acting elements within the MYCN 3-untranslated region are able to signal the degradation of stable heterologous mRNA. Ectopic overexpression of HuD dramatically inhibits RNA decay mediated by the full-length MYCN 3-untranslated region and cis-acting destabilizing elements that harbor HuD binding sites in vivo. HuD may contribute to the malignant phenotype of neuroblastoma cells by stabilizing MYCN mRNA, thereby enhancing steady-state levels of expression of this oncogene. Neuroblastoma (NB),1 a neoplasm that arises from embryonic neural crest tissue, is the second-most common solid pediatric tumor (1). MYCN is amplified in ϳ25% of primary NBs (2-4), and MYCN overexpression is frequently detected in NB tumors (5). Although the clinical significance of MYCN expression in NB tumors that lack MYCN amplification remains controversial (6 -10), a strong correlation between high levels of MYCN expression consequent to genomic amplification of this oncogene and aggressive disease is well established (3-5, 11). Laboratory experiments have further supported an important role for MYCN in determining NB phenotype. Ectopic overexpression of MYCN results in enhanced malignant growth (12, 13), whereas MYCN antisense studies performed by our laboratory and others have shown that down-regulation of MYCN in human NB is associated with a decrease in cellular proliferation and inhibited tumor cell growth in vitro (14 -16). Furthermore, a direct link between MYCN expression and the development of NB has been demonstrated in transgenic mice studies (17).Previously we examined MYCN regulation in N-(neuroblastic, tumorigenic) and S-type (substrate-adherent, non-tumorigenic) subclones (W-N and W-S) of the MYCN-amplified NB cell line NBL-W (18). In addition to distinct morphology and growth characteristics, the subclones have differential levels of MYCN expression despite having the same genomic MYCN copy number. We found that the disparity in steady-state levels of MYCN mRNA in the W-N and W-S cells was largely determined by differences in MYCN mRNA stability (19). Lazarova and co-workers (20) examined MYCN expression in other ...

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MYCN Expression Is Not Prognostic of Adverse Outcome in Advanced-Stage Neuroblastoma With Nonamplified MYCN

Abstract: High levels of MYCN expression are not prognostic of adverse outcome in patients with advanced-stage NB with nonamplified MYCN. A trend associating high levels of MYCN expression with improved outcome was observed.

Cited by 96 publications

References 44 publications

Changes in MYCN expression in human neuroblastoma cell lines following cisplatin treatment may not be related to MYCN copy numbers

Changes in MYCN expression in human neuroblastoma cell lines following cisplatin treatment may not be related to MYCN copy numbers

High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma

HuD, a Neuronal-specific RNA-binding Protein, Increases thein Vivo Stability of MYCN RNA

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