Henrich, Kai-Oliver, Bender, Sebastian, Saadati, Maral, Dreidax, Daniel, Gartlgruber, Moritz, Shao, Chunxuan, Herrmann, Carl ORCID: 0000-0003-4989-4722, Wiesenfarth, Manuel, Parzonka, Martha, Wehrmann, Lea, Fischer, Matthias, Duffy, David J., Bell, Emma, Torkov, Alica, Schmezer, Peter, Plass, Christoph, Hoefer, Thomas, Benner, Axel, Pfister, Stefan M. and Westermann, Frank (2016). Integrative Genome-Scale Analysis Identifies Epigenetic Mechanisms of Transcriptional Deregulation in Unfavorable Neuroblastomas. Cancer Res., 76 (18). S. 5523 - 5538. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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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. (C) 2016 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Henrich, Kai-OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bender, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saadati, MaralUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dreidax, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gartlgruber, MoritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shao, ChunxuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrmann, CarlUNSPECIFIEDorcid.org/0000-0003-4989-4722UNSPECIFIED
Wiesenfarth, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parzonka, MarthaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wehrmann, LeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duffy, David J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bell, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torkov, AlicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmezer, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plass, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoefer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benner, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfister, Stefan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westermann, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-262281
DOI: 10.1158/0008-5472.CAN-15-2507
Journal or Publication Title: Cancer Res.
Volume: 76
Number: 18
Page Range: S. 5523 - 5538
Date: 2016
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1538-7445
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ISLAND METHYLATOR PHENOTYPE; DNA METHYLATION; PROGNOSTIC-SIGNIFICANCE; THERAPEUTIC TARGET; GENE-EXPRESSION; CELL SIGNATURE; MYCN; CANCER; REVEALS; EZH2Multiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26228

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