PUBLICATION

MYC Drives a Subset of High-Risk Pediatric Neuroblastomas and Is Activated through Mechanisms Including Enhancer Hijacking and Focal Enhancer Amplification

Authors
Zimmerman, M.W., Liu, Y., He, S., Durbin, A.D., Abraham, B.J., Easton, J., Shao, Y., Xu, B., Zhu, S., Zhang, X., Li, Z., Weichert-Leahey, N., Young, R.A., Zhang, J., Look, A.T.
ID
ZDB-PUB-190719-25
Date
2018
Source
Cancer discovery   8: 320-335 (Journal)
Registered Authors
Durbin, Adam, He, Shuning, Li, Zhaodong, Look, A. Thomas, Zhang, Xiaoling, Zhu, Shizhen, Zimmerman, Mark
Keywords
none
Datasets
GEO:GSE101297, GEO:GSE107518
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Cell Line, Tumor
  • Child
  • Enhancer Elements, Genetic*
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Luminescent Proteins/genetics
  • N-Myc Proto-Oncogene Protein/genetics
  • Neoplasms, Experimental/genetics
  • Neuroblastoma/genetics*
  • Neuroblastoma/mortality
  • Neuroblastoma/pathology
  • Proto-Oncogene Proteins c-myc/genetics*
  • Survival Analysis
  • Translocation, Genetic
  • Zebrafish/genetics
PubMed
29284669 Full text @ Cancer Discov
Abstract
The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 253.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes