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

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

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 hypo...

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Published in:Cancer research (Chicago, Ill.) Vol. 76; no. 18; pp. 5523 - 5537
Main Authors: Henrich, Kai-Oliver, Bender, Sebastian, Saadati, Maral, Dreidax, Daniel, Gartlgruber, Moritz, Shao, Chunxuan, Herrmann, Carl, Wiesenfarth, Manuel, Parzonka, Martha, Wehrmann, Lea, Fischer, Matthias, Duffy, David J, Bell, Emma, Torkov, Alica, Schmezer, Peter, Plass, Christoph, Höfer, Thomas, Benner, Axel, Pfister, Stefan M, Westermann, Frank
Format: Journal Article
Language:English
Published: United States 15-09-2016
Subjects:
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
Neuroblastoma - mortality
Neuroblastoma - pathology
Oligonucleotide Array Sequence Analysis
Transcription, Genetic
Transcriptome
Young Adult
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Summary: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.
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ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-15-2507