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

(2008) GENOME BIOLOGY. 9(10).
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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-MY C. 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-nonamplified tumors. A defined set of MYCN/c-MYC target genes was induced in stage 4-nonamplified but not in stage 4s-non-amplified. 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 that 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.

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Chicago
Westermann, F, D Muth, A Benner, T Bauer, KO Henrich, A Oberthuer, B Brors, et al. 2008. “Distinct Transcriptional MYCN/c-MYC Activities Are Associated with Spontaneous Regression or Malignant Progression in Neuroblastomas.” Genome Biology 9 (10): R150.
APA
Westermann, F., Muth, D., Benner, A., Bauer, T., Henrich, K., Oberthuer, A., Brors, B., et al. (2008). Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas. GENOME BIOLOGY, 9(10), R150.
Vancouver
1.
Westermann F, Muth D, Benner A, Bauer T, Henrich K, Oberthuer A, et al. Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas. GENOME BIOLOGY. LONDON W1T 4LB, ENGLAND: BIOMED CENTRAL LTD, CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST,; 2008;9(10):R150.
MLA
Westermann, F, D Muth, A Benner, et al. “Distinct Transcriptional MYCN/c-MYC Activities Are Associated with Spontaneous Regression or Malignant Progression in Neuroblastomas.” GENOME BIOLOGY 9.10 (2008): R150. Print.
@article{518195,
  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-MY C. 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-nonamplified tumors. A defined set of MYCN/c-MYC target genes was induced in stage 4-nonamplified but not in stage 4s-non-amplified. 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 that 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.},
  author       = {Westermann, F and Muth, D and Benner, A and Bauer, T and Henrich, KO and Oberthuer, A and Brors, B and Beissbarth, T and Vandesompele, Jo and Pattyn, Filip and Hero, B and Konig, R and Fischer, M and Schwab, M},
  issn         = {1474-760X},
  journal      = {GENOME BIOLOGY},
  language     = {eng},
  number       = {10},
  publisher    = {BIOMED CENTRAL LTD, CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST,},
  title        = {Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas},
  volume       = {9},
  year         = {2008},
}

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