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

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.

• Authors: Frank Westermann, Daniel Muth, Axel Benner, Tobias Bauer, Kai-Oliver Henrich, André Oberthuer, Benedikt Brors, Tim Beissbarth, Jo Vandesompele, Filip Pattyn, Barbara Hero, Rainer König, Matthias Fischer, Manfred Schwab
• Journal: Genome biology (Genome Biol) Vol. 9 Issue 10 Pg. R150 (Oct 13 2008) ISSN: 1474-760X [Electronic] England
• PMID: 18851746 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MYC protein, human
• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Nuclear Proteins
• Oncogene Proteins
• Proto-Oncogene Proteins c-myc

Topics

• Disease Progression
• Gene Expression Regulation, Neoplastic
• Genes, myc
• N-Myc Proto-Oncogene Protein
• Neuroblastoma (genetics, pathology)
• Nuclear Proteins (genetics, metabolism)
• Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Survival Analysis
• Transcription, Genetic
• Tumor Cells, Cultured