Abstract
MYCN amplification strongly predicts adverse outcome of neuroblastoma. However, the significance of MYCN expression in the clinical and biological behavior of neuroblastoma has been unclear. To address this question, we first examined the expression of MYCN in combination with TrkA (a favorable prognostic indicator of neuroblastoma) in 91 primary neuroblastoma by quantitative reverse transcription-PCR and investigated the relationship among patient survival, MYCN, and TrkA expressions. Three subsets of neuroblastoma were defined based on MYCN and TrkA expression. Neuroblastoma expressing the highest level of MYCN but little TrkA were MYCN-amplified cases, which had a 5-year survival of 9.3%. Interestingly, MYCN and TrkA expression showed a linear correlation (r = 0.5664, P < 0.00005) in neuroblastoma lacking MYCN amplification, and the 5-year survival of neuroblastoma patients with low MYCN and low TrkA expressions was 63.7%, whereas those with high expression of both had a 5-year survival of 88.1% (P < 0.00005). This nonlinear distribution of disease outcome relative to MYCN expression in neuroblastoma explains why MYCN expression is not predictive of neuroblastoma disease outcome by dichotomous division of the neuroblastoma cohort. However, high-level MYCN expression is associated with favorable outcome in neuroblastoma lacking MYCN amplification. Furthermore, forced expression of MYCN significantly suppresses growth of neuroblastoma cells lacking MYCN amplification by inducing apoptosis and enhancing favorable neuroblastoma gene expression. Collectively, these data suggest that high-level MYCN expression in neuroblastoma lacking MYCN amplification results in a benign phenotype. Thus, the high MYCN expression confers the opposite biological consequence in neuroblastoma, depending on whether or not MYCN is amplified.
Highlights
Neuroblastoma is a common pediatric solid tumor of neural crest origin
MYCN amplification was identified in neuroblastoma by Schwab et al over 20 years ago [39]
A series of studies have been conducted to address the prognostic significance of MYCN expression in neuroblastoma [13, 19,20,21, 24,25,26,27,28,29]
Summary
Neuroblastoma is a common pediatric solid tumor of neural crest origin. The tumor occurs in infants and young children with primary sites in adrenal glands or the sympathetic chain. There are additional genetic and biological markers of neuroblastoma that are predictive of disease outcome These include deletion or allelic loss of chromosome 1p or 11q [8,9,10,11], allelic gain of 17q [12], and the expression of transcripts encoding receptor tyrosine kinases (TrkA and EPHB6) and cell surface molecules (CD44, EFNB2, and EFNB3). These five genes in particular have been defined as favorable neuroblastoma genes, because high-level expression of these genes predicts favorable outcome of neuroblastoma clinically and suppresses growth of unfavorable neuroblastoma cells in vitro and in mouse xenograft models [13,14,15,16,17]. When one of the favorable neuroblastoma genes is expressed at high levels, patient disease outcome is favorable [15]
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