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

Abstract

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

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

“…It also confirms that assessing entire signaling pathways, rather than individual genes, is highly informative with respect to cancer outcome prediction (Bild et al, 2006;Watters and Roberts, 2006;Liu and Ringner, 2007). For neuroblastoma in particular, combined analysis of multiple signaling networks has been successful and might benefit from the addition of other pathways, such as integrin signaling, to further increase prediction sensitivity (Fredlund et al, 2008). In addition, the observed similarities in miRNA expression between MNA and SH neuroblastoma tumors suggest that both tumor subgroups share a number of pathways deregulated through MYCN/c-MYC-mediated miRNA modulation.…”

“…Patients in the first quartile, representing tumors with the lowest expression of predicted 8mer miRNA targets, have a particular poor prognosis as compared with those in the fourth quartile. Of interest, 48% of the tumors in the first quartile (n ¼ 66) were MYCN single-copy confirming that MYCN/c-MYC signaling rather than MYCN amplification underlies the poor outcome of these patients (Fredlund et al, 2008;Westermann et al, 2008). Moreover, 8mer miRNA-mediated target repression but not MYCN amplification status was an independent factor in a multivariate Cox regression model for EFS and OS (Supplementary Table S3).…”

“…The combined activity of the predicted 8mer miRNA targets (n ¼ 193) was evaluated using a rank-based pathway score in two independent neuroblastoma microarray data sets (Oberthuer et al, 2006;Wang et al, 2006). To assess the effect on patient outcome, samples were divided into quartiles according to the pathway activity score (Fredlund et al, 2008). Kaplan-Meier analysis of the Oberthuer data based on these quartiles revealed a significant correlation to both event-free (EFS, Po0.001) and overall survival (OS, Po0.001) (Figures 5a and b).…”

“…Activated MYCN/c-MYC signaling is a hallmark of poor prognosis for neuroblastoma tumors (Fredlund et al, 2008) and can be caused either by MYCN amplification (Seeger et al, 1985) or increased c-MYC expression in stage 4 MYCN non-amplified neuroblastoma tumors (Westermann et al, 2008). This increase in MYCN/c-MYC expression results in the activation of coding target genes related to poor patient prognosis independently of MYCN amplification (Fredlund et al, 2008;Westermann et al, 2008).…”

Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

“…[2][3][4][5] Earlier reports have identified that in neuroblastoma the expression of markers that are upregulated in later stages of the neuronal lineage of sympathetic nervous system differentiation, such as neurotrophic tyrosine kinase, receptor, type 1 (NTRK1) and growth-associated protein 43 (GAP43), is indicative of better prognosis. 6,7 The age of patient, genetic aberrations (N-MYC amplification and deletion of chromosome 11 q) and metastatic spread are important factors with regard to treatment decision and patient prognosis. The International Neuroblastoma Staging System is divided into 1-4 stage groups and stage 4 S, which has the ability to spontaneously regress.…”