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  • American Association for Cancer Research (AACR)  (4)
  • 2015-2019  (4)
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  • American Association for Cancer Research (AACR)  (4)
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  • 2015-2019  (4)
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  • 1
    Online Resource
    Online Resource
    Abstract 1426: Blinding the CYCLOPS - Cancer vulnerabilities unveiled by genomic loss
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1426-1426
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1426-1426
    Abstract: Background: Heterozygous deletions within distal 1p are observed in 30% of neuroblastomas. So far, several potential 1p tumor suppressor genes have been identified. However, in this study we are focussing on 1p genes whose inactivation is not necessarily linked to tumor development but which mediate cell-essential functions, rendering cells with copy number loss vulnerable to further impairment. These genes are candidate therapeutic targets according to the concept of CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss). Methods: To identify a subset of 1p genes for which heterozygous loss may be tolerated but further reduction leads to cell death, we performed siRNA screens mediating the systematic knock-down of distal 1p genes in five 1p-deleted versus five non-1p-deleted neuroblastoma cell lines. We used 3 different siRNAs per gene in a liquid forward approach. After 96h Hoechst stained nuclei were count. Among others, a neuron-related candidate gene has been identified as a potential CYCLOPS. The candidate gene was validated by viability assays, immunocytochemistry and cell cycle analysis via FACS. Results: We identified many potential CYCLOPS genes mapping on the distal end of chromosome arm 1p. One of these genes is involved in neuronal and embryonic development and has been further validated. Knock-down of the gene impaired cell viability in 1p-deleted cell lines but did not in 1p-non-deleted cells. G1/G0 phase arrest with corresponding S phase decrease was observed in both 1p-deleted and 1p-non-deleted cells. Additionally, neurite-like outgrowth could be observed in 1p-non-deleted cells indicating an induction of differentiation. Conclusion: This study identified a candidate CYCLOPS gene in neuroblastoma. Heterozygous deletions of chromosome arm 1p are also frequently observed in other cancers including melanoma, colorectal and breast cancer. We hypothesize that this proof-of-principle opens a new therapeutic window for tumors harbouring a heterozygous deletion of our candidate gene or other cell essential genes on chromosome arm 1p. Citation Format: Alica Torkov, Kai-Oliver Henrich, Chunxuan Shao, Moritz Gartlgruber, Frank Westermann. Blinding the CYCLOPS - Cancer vulnerabilities unveiled by genomic loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1426. doi:10.1158/1538-7445.AM2017-1426
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-1426
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract LB-083: Core transcriptional regulatory circuitries in neuroblastoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. LB-083-LB-083
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. LB-083-LB-083
    Abstract: Background Neuroblastoma (NB) is a pediatric tumor derived from precursor cells of the sympathetic nervous system. NB accounts for 12% of all childhood cancer deaths with ~50% high-risk cases which frequently harbor amplified proto-oncogene MYCN. Evidence accumulates that epigenetic deregulation, including aberrant DNA methylation in high-risk disease or oncogene activation by enhancer hijacking, plays a prominent role in NB. The present study applies a comprehensive approach integrating chromatin modification data with genomic and expression data to elucidate NB subtype specific super-enhancer (SE) landscapes and core regulatory circuitries (CRCs) consisting of lineage-specific interconnected loops of SE-driven, auto-regulatory master transcription factors. Methods Chromatin immunoprecipitation sequencing (ChIP-seq) of histone 3 lysine 27 acetylation (H3K27ac) was used to identify active enhancer elements in 23 primary NBs. A validation cohort consisting of 16 NB cell lines and two human neural crest cell lines was used. ChIPmentation was applied to validate predicted transcription factor (TF) binding events. Circular chromatin conformation capture sequencing (4C-seq) was used to assay physical promoter-enhancer interactions. Results Unsupervised clustering of 23 primary NBs according to H3K27ac signal intensity at the most variable SEs (genome-wide) revealed two main subgroups, MYCN-amplified (n = 8) and MYCN single copy tumors (n = 15), with distinctive activity patterns. Calling of CRCs in the 23 primary NBs yielded a core set of NB master TFs (CRC TFs). Amongst the top ten of them are HAND2, PHOX2B and MYCN, all of which are implicated in NB biology and playing essential roles in the development of the sympathetic nervous system. In line with this, gene ontology analyses of the top 50 CRC TFs converge on biological processes like development of neural crest cells, sympathetic nervous system and peripheral nervous system neurons. ChIPmentation analyses of selected CRC TFs confirmed auto-binding to their assigned SEs and those of other CRC TFs in their respective network. Interactions between promoters and SEs of selected CRC TFs were verified via 4C-seq. Intriguingly, expression analysis of the top 50 CRC TFs in a cohort of 498 primary NBs revealed that less than 20% of the CRC TFs are up-regulated in MYCN-amplified tumors while the remaining 80% are down-regulated in that subgroup. This suggests a superordinate role of MYCN in differentially orchestrating NB master TFs. Conclusion The study identifies the core set of NB master transcription factors and assigns established NB regulators like HAND2, PHOX2B and MYCN to well-defined CRCs. It reveals an association of MYCN amplification with the global SE landscape of primary NBs and suggests a role for MYCN in differentially controlling subsets of CRC TFs and their networks. Specific targeting of the SE-dependent CRC networks may open a therapeutic window for epigenetic drugs, including BET inhibitors, CDK7 or EZH2 inhibition, in NB. Citation Format: Moritz Gartlgruber, Daniel Dreidax, Daria Doncevic, Sebastian Steinhauser, Stefan Gröschel, Kai Oliver Henrich, Young-Gyu Park, Carl Herrmann, Frank Westermann. Core transcriptional regulatory circuitries in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-083. doi:10.1158/1538-7445.AM2017-LB-083
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-LB-083
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Abstract 1023: Activation of proto-oncogenes by enhancer-hijacking in high-risk neuroblastoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1023-1023
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1023-1023
    Abstract: Background: Neuroblastoma (NB), a neural crest-derived tumor of the sympathetic nervous system, is the most common extracranial solid tumor in children. We have previously shown that genomic rearrangements activate proto-oncogenic telomerase by juxtaposing active enhancer elements to the TERT gene in a large fraction of high-risk NBs. In the present study, we applied a global approach integrating whole genome sequencing (WGS), Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) data of NB cells and tumors to identify further key oncogenes activated by enhancer-hijacking in NB. Methods: WGS was applied to search for structural rearrangements in 120 NB tumors and five NB cell lines. Corresponding RNA-seq data were used to discover mono-allelic and/or outlier expression of candidate genes potentially involved in enhancer hijacking events. ChIP-seq of 34 NB tumors and 17 NB cell lines was applied to identify active enhancer elements in NB. Circular chromatin conformation capture sequencing (4C-seq) was used to confirm physical promoter-enhancer interactions in NB cell lines. Results: WGS analyses revealed that chromosomal rearrangements are common events in NB tumors and cell lines and frequently affect regions harboring proto-oncogenes and lineage specific enhancers. ChIP-seq analyses of the chromatin mark histone 3 lysine 27 acetylation (H3K27ac), surrogate for enhancer activity, confirmed that these rearrangements recurrently juxtapose active enhancer elements to oncogenes including MYCN and MYC in NB. Intriguingly, quantification of H3K27ac ChIP-seq profiles uncovered that the enhancer elements translocated to MYC were among the most active ones within the respective epigenomes. 4C-seq analyses proofed physical interactions between translocated enhancer elements and promoters of the respective oncogenes, which is in line with their elevated expression in rearranged cases. Conclusions: Our study reveals that structural rearrangements in high-risk neuroblastoma frequently juxtapose strong enhancers to key oncogenes, including MYCN and MYC, leading to physical promoter-enhancer interactions which likely drive overexpression of the oncogenes observed in rearranged cases. The common mechanism of oncogene activation by enhancer-hijacking may open a therapeutic window for epigenetic drugs including BET or CDK7 inhibitors in high-risk NBs. Citation Format: Daniel Dreidax, Moritz Gartlgruber, Sebastian Steinhauser, Larisa Savelyeva, Ron Schwessinger, Umut Toprak, Nati Ha, Dilafruz Juraeva, Martin Peifer, Matthias Fischer, Stefan Gröschel, Kai-Oliver Henrich, Young-Gyu Park, Benedikt Brors, Matthias Schlesner, Carl Herrmann, Frank Westermann. Activation of proto-oncogenes by enhancer-hijacking in high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1023. doi:10.1158/1538-7445.AM2017-1023
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-1023
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Integrative Genome-Scale Analysis Identifies Epigenetic Mechanisms of Transcriptional Deregulation in Unfavorable Neuroblastomas
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 18 ( 2016-09-15), p. 5523-5537
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 18 ( 2016-09-15), p. 5523-5537
    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.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-2507
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
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