Abstract
Neuroblastoma is an embryonic tumor arising from immature sympathetic nervous system cells. Recurrent genomic alterations include MYCN and ALK amplification as well as recurrent patterns of gains and losses of whole or large partial chromosome segments. A recent whole genome sequencing effort yielded no frequently recurring mutations in genes other than those affecting ALK. However, the study further stresses the importance of DNA copy number alterations in this disease, in particular for genes implicated in neuritogenesis. Here we provide additional evidence for the importance of focal DNA copy number gains and losses, which are predominantly observed in MYCN amplified tumors. A focal 5 kb gain encompassing the MYCN regulated miR-17~92 cluster as sole gene was detected in a neuroblastoma cell line and further analyses of the array CGH data set demonstrated enrichment for other MYCN target genes in focal gains and amplifications. Next we applied an integrated genomics analysis to prioritize MYCN down regulated genes mediated by MYCN driven miRNAs within regions of focal heterozygous or homozygous deletion. We identified RGS5, a negative regulator of G-protein signaling implicated in vascular normalization, invasion and metastasis, targeted by a focal homozygous deletion, as a new MYCN target gene, down regulated through MYCN activated miRNAs. In addition, we expand the miR-17~92 regulatory network controlling TGFß signaling in neuroblastoma with the ring finger protein 11 encoding gene RNF11, which was previously shown to be targeted by the miR-17~92 member miR-19b. Taken together, our data indicate that focal DNA copy number imbalances in neuroblastoma (1) target genes that are implicated in MYCN signaling, possibly selected to reinforce MYCN oncogene addiction and (2) serve as a resource for identifying new molecular targets for treatment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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DNA Copy Number Variations*
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Down-Regulation
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Gene Expression Regulation, Neoplastic*
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Homozygote
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Humans
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MicroRNAs / genetics
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MicroRNAs / metabolism
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N-Myc Proto-Oncogene Protein
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Neuroblastoma / genetics*
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Neuroblastoma / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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RGS Proteins / genetics
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RGS Proteins / metabolism
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RNA, Long Noncoding
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Signal Transduction
Substances
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MIR17HG, human
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MYCN protein, human
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MicroRNAs
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N-Myc Proto-Oncogene Protein
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Nuclear Proteins
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Oncogene Proteins
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RGS Proteins
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RGS5 protein, human
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RNA, Long Noncoding
Grants and funding
CK is indebted to the Institute for the Promotion of Innovation by Science and Technology (IWT-Vlaanderen;
http://www.iwt.be/) for a predoctoral fellowship (grant number 081373), AF, KD, PM, and FP are supported by the Fund for Scientific Research Flanders (FWO;
http://www.fwo.be/). SD is supported by an “Emmanuel van der Schueren” grant from the “Vlaamse Liga tegen Kanker” (
http://www.tegenkanker.be/). This work was supported by the European Union (STREP-EET project, grant number 037260;
http://ec.europa.eu/research/index.cfm), the FWO (grant number: G.0198.08), the Belgian program of Interuniversity Poles of Attraction (IUAP;
http://www.belspo.be/belspo/iap/index_en.stm), initiated by the Belgian State, Prime Minister's Office, Science Policy Programming, by the GOA (
http://www.ugent.be/nl/onderzoek/financiering/bof/GOA; grant number 01G01910), the FOD (
http://www.health.belgium.be/eportal; grant number: NKP_29_014) and the IWT (grant number: SBO60848). This work was also funded by the department of Pathology, Medical School, University of Valencia, Valencia, Spain: RD06/0020/0102 and PI10/0015 (ISCIII & ERDF); 396/2009 (FAECC). The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007–2013) under grant agreement n°259348 (ASSET). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.