Log on / register
BioMed Central home | Journals A-Z | Feedback | Support | My details
.refereed research
 |  |  |  |  | 


Open AccessResearch

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

Frank Westermann1* email, Daniel Muth1* email, Axel Benner2 email, Tobias Bauer3 email, Kai-Oliver Henrich1 email, André Oberthuer4 email, Benedikt Brors3 email, Tim Beissbarth5 email, Jo Vandesompele6 email, Filip Pattyn6 email, Barbara Hero4 email, Rainer König3 email, Matthias Fischer4 email and Manfred Schwab1 email

Department of Tumor Genetics, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

Department of Biostatistics, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

Theoretical Bioinformatics, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

Department of Pediatric Oncology, University Children's Hospital of Cologne, Kerpener Strasse 62, Cologne, 50924, Germany

Division of Molecular Genome Analysis, German Cancer Research Center, Im Neuenheimer Feld 580, Heidelberg, 69120, Germany

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.


© 1999-2010 BioMed Central Ltd unless otherwise stated. Part of Springer Science+Business Media.