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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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
7 September 2016
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| In: |
Cancer research
Year: 2016, Volume: 76, Issue: 18, Pages: 5523-5537 |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-15-2507 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1158/0008-5472.CAN-15-2507 Verlag, kostenfrei, Volltext: http://cancerres.aacrjournals.org/content/76/18/5523 
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| Author Notes: | 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, and Frank Westermann |
| 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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| Item Description: | Gesehen am 21.12.2017 |
| Physical Description: | Online Resource |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-15-2507 |