Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Integrated bioinformatic and wet-lab approach to identify potential oncogenic networks in neuroblastoma

ABSTRACT: mRNA profiles of thousands of human tumors are available, but methods to deduce oncogenic signaling networks from these data lag behind. It is especially challenging to identify main-regulatory routes, and to generalize conclusions obtained from experimental models. We designed the bioinformatic platform R2 in parallel with a wet-lab approach of neuroblastoma. Here we demonstrate how R2 facilitates an integrated analysis of our neuroblastoma data. Analysis of the MYCN pathway suggested important regulatory connections to the polyamine synthesis route, the Notch pathway and the BMP/TGFM-NM-2 pathway. A network of genes emerged connecting major oncogenes in neuroblastoma. Genes in the network carried strong prognostic values and were essential for tumor cell survival. 88 human Neuroblastoma samples were analyzed.

ORGANISM(S): Homo sapiens

SUBMITTER: Rogier Versteeg

PROVIDER: E-GEOD-16476 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.

Molenaar Jan J JJ Koster Jan J Zwijnenburg Danny A DA van Sluis Peter P Valentijn Linda J LJ van der Ploeg Ida I Hamdi Mohamed M van Nes Johan J Westerman Bart A BA van Arkel Jennemiek J Ebus Marli E ME Haneveld Franciska F Lakeman Arjan A Schild Linda L Molenaar Piet P Stroeken Peter P van Noesel Max M MM Ora Ingrid I Santo Evan E EE Caron Huib N HN Westerhout Ellen M EM Versteeg Rogier R

Nature 20120222 7391

Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defec ...[more]

PMID: 22367537

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Project description:Neuroblastoma tumors frequently show loss of heterozygosity of chromosome 11q with a shortest region of overlap in the 11q23 region. These deletions are thought to cause inactivation of tumor suppressor genes leading to haploinsufficiency. Alternatively, micro-deletions could lead to gene fusion products that are tumor-driving. To identify such events we analyzed a series of neuroblastomas by comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays and integrated these data with Affymetrix mRNA profiling data with the bioinformatic tool R2 (http://r2.amc.nl). We identified three neuroblastoma samples with small interstitial deletions at 11q23, upstream of the forkhead-box transcription factor FOXR1. Genes at the proximal side of the deletion were fused to FOXR1, resulting in fusion transcripts of MLL-FOXR1 and PAFAH1B2-FOXR1. FOXR1 expression has only been detected in early embryogenesis. Affymetrix microarray analysis showed high FOXR1 mRNA expression exclusively in the neuroblastomas with micro-deletions and rare cases of other tumor types, including osteosarcoma cell line HOS. RNAi silencing of FOXR1 strongly inhibited proliferation of HOS cells and triggered apoptosis. Expression profiling of these cells and reporter assays suggested that FOXR1 is a negative regulator of forkhead-box factor mediated transcription. The neural crest stem cell line JoMa1 proliferates in culture conditional to activity of a MYC-ER transgene. Over-expression of the wild-type FOXR1 could functionally replace MYC and drive proliferation of JoMa1. We conclude that FOXR1 is recurrently activated in neuroblastoma by intrachromosomal deletion/fusion events, resulting in over-expression of fusion transcripts. Forkhead-box transcription factors have not been previously implicated in neuroblastoma pathogenesis. Furthermore, this is the first identification of intrachromosomal fusion genes in neuroblastoma. Time series Affymetrix U133p2 profiling of Osteosarcoma HOS cells transduced with FOXR1 targeted shRNAs or control shRNA

Dataset Information

Integrated bioinformatic and wet-lab approach to identify potential oncogenic networks in neuroblastoma

Publications

Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.

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