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.