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High Skp2 Expression Characterizes High-Risk Neuroblastomas Independent of MYCN Status

Authors' Affiliations: ¹ Department of Tumor Genetics, German Cancer Research Center, Heidelberg, Germany; ² Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland; ³ Institute of Molecular Biology and Tumor Research, University of Marburg, Marburg, Germany; ⁴ Department of Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany; ⁵ Theoretical Bioinformatics, German Cancer Research Center; ⁶ Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and ⁷ Department of Pathology, University of Heidelberg; ⁸ Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany; and ⁹ Department of Pathology, University of Kiel, Kiel, Germany

Requests for reprints: Frank Westermann, Department of Tumour Genetics, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, BW 69221, Germany. Phone: 49-622-1423275; E-mail: f.westermann{at}dkfz.de.

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusion: Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches.