Research

Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas

Frank Westermann^1* , Daniel Muth^1* , Axel Benner² , Tobias Bauer³ , Kai-Oliver Henrich¹ , André Oberthuer⁴ , Benedikt Brors³ , Tim Beissbarth⁵ , Jo Vandesompele⁶ , Filip Pattyn⁶ , Barbara Hero⁴ , Rainer König³ , Matthias Fischer⁴ and Manfred Schwab¹

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

author email corresponding author email* Contributed equally

Genome Biology 2008, 9:R150doi:10.1186/gb-2008-9-10-r150

Published:	13 October 2008

Subject areas: Cancer, Genome studies, Molecular biology

Abstract

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.