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.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.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.
%0 Journal Article
%1 Westermann2008
%A Westermann, Frank
%A Muth, Daniel
%A Benner, Axel
%A Bauer, Tobias
%A Henrich, Kai-Oliver
%A Oberthuer, André
%A Brors, Benedikt
%A Beissbarth, Tim
%A Vandesompele, Jo
%A Pattyn, Filip
%A Hero, Barbara
%A König, Rainer
%A Fischer, Matthias
%A Schwab, Manfred
%D 2008
%J Genome Biol
%K Analysis; Cells, Cultured Disease Expression Gene Genes, Genetic; Neoplastic; Neuroblastoma, Nuclear Oncogene Progression; Proteins Proteins, Proto-Oncogene Regulation, Survival Transcription, Tumor c-myc, genetics/metabolism; genetics/pathology; myc;
%N 10
%P R150
%R 10.1186/gb-2008-9-10-r150
%T Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas.
%U http://dx.doi.org/10.1186/gb-2008-9-10-r150
%V 9
%X 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.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.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.
@article{Westermann2008,
__markedentry = {[bbrors:6]},
abstract = {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.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.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.},
added-at = {2015-04-09T12:36:21.000+0200},
author = {Westermann, Frank and Muth, Daniel and Benner, Axel and Bauer, Tobias and Henrich, Kai-Oliver and Oberthuer, Andr{\'{e}} and Brors, Benedikt and Beissbarth, Tim and Vandesompele, Jo and Pattyn, Filip and Hero, Barbara and K{\"{o}}nig, Rainer and Fischer, Matthias and Schwab, Manfred},
biburl = {https://www.bibsonomy.org/bibtex/295bc5c01af1a5a6e0ef345a9b5c75fa7/bbrors},
doi = {10.1186/gb-2008-9-10-r150},
institution = {Department of Tumor Genetics, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Germany. f.westermann@dkfz.de},
interhash = {d293fcc89b51060cfbbceb49365c6730},
intrahash = {95bc5c01af1a5a6e0ef345a9b5c75fa7},
journal = {Genome Biol},
keywords = {Analysis; Cells, Cultured Disease Expression Gene Genes, Genetic; Neoplastic; Neuroblastoma, Nuclear Oncogene Progression; Proteins Proteins, Proto-Oncogene Regulation, Survival Transcription, Tumor c-myc, genetics/metabolism; genetics/pathology; myc;},
language = {eng},
medline-pst = {epublish},
number = 10,
owner = {bbrors},
pages = {R150},
pii = {gb-2008-9-10-r150},
pmid = {18851746},
timestamp = {2015-04-09T12:36:21.000+0200},
title = {Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas.},
url = {http://dx.doi.org/10.1186/gb-2008-9-10-r150},
volume = 9,
year = 2008
}