Research
Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas
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* Corresponding author: Frank Westermann f.westermann@dkfz.de
- † Equal contributors
1 Department of Tumor Genetics, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany
2 Department of Biostatistics, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany
3 Theoretical Bioinformatics, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany
4 Department of Pediatric Oncology, University Children's Hospital of Cologne, Kerpener Strasse 62, Cologne, 50924, Germany
5 Division of Molecular Genome Analysis, German Cancer Research Center, Im Neuenheimer Feld 580, Heidelberg, 69120, Germany
6 Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, Ghent, 9000, Belgium
Genome Biology 2008, 9:R150 doi:10.1186/gb-2008-9-10-r150
Published: 13 October 2008Abstract
Background
Amplified MYCN oncogene resulting in deregulated MYCN transcriptional activity is observed in 20% of neuroblastomas and identifies a highly aggressive subtype. In MYCN single-copy neuroblastomas, elevated MYCN mRNA and protein levels are paradoxically associated with a more favorable clinical phenotype, including disseminated tumors that subsequently regress spontaneously (stage 4s-non-amplified). In this study, we asked whether distinct transcriptional MYCN or c-MYC activities are associated with specific neuroblastoma phenotypes.
Results
We defined a core set of direct MYCN/c-MYC target genes by applying gene expression profiling and chromatin immunoprecipitation (ChIP, ChIP-chip) in neuroblastoma cells that allow conditional regulation of MYCN and c-MYC. Their transcript levels were analyzed in 251 primary neuroblastomas. Compared to localized-non-amplified neuroblastomas, MYCN/c-MYC target gene expression gradually increases from stage 4s-non-amplified through stage 4-non-amplified to MYCN amplified tumors. This was associated with MYCN activation in stage 4s-non-amplified and predominantly c-MYC activation in stage 4-non-amplified tumors. A defined set of MYCN/c-MYC target genes was induced in stage 4-non-amplified but not in stage 4s-non-amplified neuroblastomas. In line with this, high expression of a subset of MYCN/c-MYC target genes identifies a patient subtype with poor overall survival independent of the established risk markers amplified MYCN, disease stage, and age at diagnosis.
Conclusions
High MYCN/c-MYC target gene expression is a hallmark of malignant neuroblastoma progression, which is predominantly driven by c-MYC in stage 4-non-amplified tumors. In contrast, moderate MYCN function gain in stage 4s-non-amplified tumors induces only a restricted set of target genes that is still compatible with spontaneous regression.