Abstract
Amplified MYCN oncogene defines a subgroup of neuroblastomas with poor outcome. However, a substantial number of MYCN single-copy neuroblastomas exhibits an aggressive phenotype similar to that of MYCN-amplified neuroblastomas even in the absence of high MYCN mRNA and/or protein levels. To identify shared molecular mechanisms that mediate the aggressive phenotype in MYCN-amplified and single-copy high-risk neuroblastomas, we defined genetic programs evoked by ectopically expressed MYCN in vitro and analyzed them in high-risk versus low-risk neuroblastoma tumors (n = 49) using cDNA microarrays. Candidate gene expression was validated in a separate cohort of 117 patients using quantitative PCR, and protein expression was analyzed in neuroblastoma tumors by immunoblotting and immunohistochemistry. We identified a genetic signature characterized by a subset of MYCN/MYC and E2F targets, including Skp2, encoding the F-box protein of the SCF(Skp2) E3-ligase, to be highly expressed in high-risk neuroblastomas independent of amplified MYCN. We validated the findings for Skp2 and analyzed its expression in relation to MYCN and E2F-1 expression in a separate cohort (n = 117) using quantitative PCR. High Skp2 expression proved to be a highly significant marker of dire prognosis independent of both MYCN status and disease stage, on the basis of multivariate analysis of event-free survival (hazard ratio, 3.54; 95% confidence interval, 1.56-8.00; P = 0.002). Skp2 protein expression was inversely correlated with expression of p27, the primary target of the SCF(Skp2) E3-ligase, in neuroblastoma tumors. Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches.
Highlights
Amplified MYCN oncogene defines a subgroup of neuroblastomas with poor outcome
Using cDNA microarray analysis of neuroblastoma cells after conditional expression of MYCN in vitro and of 49 primary neuroblastoma tumors, we identified a subset of direct MYCN/MYC and E2F targets that provided information on patients’ outcome to genomic MYCN status or MYCN expression
We found that transcript profiling of a neuroblastoma in vitro system that allows conditional expression of MYCN delineates MYCN downstream genetic programs that are associated with patients’ outcome independent of genomic MYCN status
Summary
Amplified MYCN oncogene defines a subgroup of neuroblastomas with poor outcome. a substantial number of MYCN single-copy neuroblastomas exhibits an aggressive phenotype similar to that of MYCN-amplified neuroblastomas even in the absence of high MYCN mRNA and/or protein levels. A considerable number of MYCN single-copy neuroblastomas exhibits an aggressive phenotype similar to that of MYCN-amplified tumors even in the absence of high MYCN mRNA and/or protein levels [6, 7], suggesting other unfavorable molecular abnormalities that could account for the inferior survival. A consistent finding from these studies was that a subset of cell cycle genes are expressed at higher levels in high-risk neuroblastomas independent of the genomic MYCN status. Due to the absence of high MYCN levels in MYCN single-copy high-risk neuroblastomas, it is not clear whether activation of MYCN-regulated genes plays a significant role in uncontrolled cell cycle progression in this neuroblastoma subtype
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