title: Focal DNA copy number changes in neuroblastoma target MYCN regulated genes.
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.
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Candy
authors: C
authors: Kumps
authors: Annelies
authors: A
authors: Fieuw
authors: Pieter
authors: P
authors: Mestdagh
authors: Björn
authors: B
authors: Menten
authors: Steve
authors: S
authors: Lefever
authors: Filip
authors: F
authors: Pattyn
authors: Sara
authors: S
authors: De Brouwer
authors: Tom
authors: T
authors: Sante
authors: Johannes Hubertus
authors: JH
authors: Schulte
authors: Alexander
authors: A
authors: Schramm
authors: Nadine
authors: N
authors: Van Roy
authors: Tom
authors: T
authors: Van Maerken
authors: Rosa
authors: R
authors: Noguera
authors: Valérie
authors: V
authors: Combaret
authors: Christine
authors: C
authors: Devalck
authors: Frank
authors: F
authors: Westermann
authors: Geneviève
authors: G
authors: Laureys
authors: Angelika
authors: A
authors: Eggert
authors: Jo
authors: J
authors: Vandesompele
authors: Katleen
authors: K
authors: De Preter
authors: Frank
authors: F
authors: Speleman
mesh_terms: D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006720:Homozygote; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding; D015398:Signal Transduction
chemical_list: C568997:MIR17HG, human; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D020710:RGS Proteins; C491349:RGS5 protein, human; D062085:RNA, Long Noncoding