%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 }