Integrative Genome-Scale Analysis Identifies Epigenetic Mechanisms of Transcriptional Deregulation in Unfavorable Neuroblastomas.

Abstract

The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility of epigenetic involvement in pathogenesis. In pursuit of this hypothesis, we took an integrative approach to analyze the methylomes, transcriptomes, and copy number variations in 105 cases of neuroblastoma, complemented by primary tumor- and cell line-derived global histone modification analyses and epigenetic drug treatment in vitro We found that DNA methylation patterns identify divergent patient subgroups with respect to survival and clinicobiologic variables, including amplified MYCN Transcriptome integration and histone modification-based definition of enhancer elements revealed intragenic enhancer methylation as a mechanism for high-risk-associated transcriptional deregulation. Furthermore, in high-risk neuroblastomas, we obtained evidence for cooperation between PRC2 activity and DNA methylation in blocking tumor-suppressive differentiation programs. Notably, these programs could be re-activated by combination treatments, which targeted both PRC2 and DNA methylation. Overall, our results illuminate how epigenetic deregulation contributes to neuroblastoma pathogenesis, with novel implications for its diagnosis and therapy. Cancer Res; 76(18); 5523-37. ©2016 AACR.

• Authors: Kai-Oliver Henrich, Sebastian Bender, Maral Saadati, Daniel Dreidax, Moritz Gartlgruber, Chunxuan Shao, Carl Herrmann, Manuel Wiesenfarth, Martha Parzonka, Lea Wehrmann, Matthias Fischer, David J Duffy, Emma Bell, Alica Torkov, Peter Schmezer, Christoph Plass, Thomas Höfer, Axel Benner, Stefan M Pfister, Frank Westermann
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 18 Pg. 5523-37 (09 15 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27635046 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• MYCN protein, human
• N-Myc Proto-Oncogene Protein

Topics

• Adolescent
• Cell Line, Tumor
• Child
• Child, Preschool
• Chromatin Immunoprecipitation
• Cluster Analysis
• DNA Methylation (genetics)
• Epigenesis, Genetic (genetics)
• Female
• Genome-Wide Association Study
• High-Throughput Nucleotide Sequencing
• Humans
• Infant
• Infant, Newborn
• Kaplan-Meier Estimate
• Male
• N-Myc Proto-Oncogene Protein (genetics)
• Neuroblastoma (genetics, mortality, pathology)
• Oligonucleotide Array Sequence Analysis
• Transcription, Genetic
• Transcriptome
• Young Adult