Abstract

Neuroblastoma are a childhood tumors 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 tumor. Frequently detected gene alterations were limited to MYCN amplification and ALK activations. Our recent studies on the genomic landscape of primary neuroblastoma revealed two novel molecular defects. The analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis in 18% of high stage neuroblastoma. These tumors are associated with a poor outcome. In addition, an integrated analysis of mutation data and structural aberration data showed frequent alterations in genes involved in neuritogenesis (1). Despite these newly identified genomic aberrations the absolute number of genomic aberrations in neuroblastoma is much lower compared to adult tumors. Whole genome sequencing of multiple subclones of the same primary tumor showed that in some neuroblastoma tumors we could not detect any early tumor driving mutations. Therefore these tumors are most likely depending on copy number aberrations and structural variations for tumor initiation. Also sequence efforts in other pediatric cancers showed a low frequency of early tumor driving mutations. This urges an approach in which individualized therapeutic strategies in pediatric cancer not only use strong biomarkers as activating gene mutations. Also synthetic lethal combinations and milder aberrations as copy number gains and epigenetic aberrations should be explored as biomarkers for targeted therapy. We have now validated a series of target genes and corresponding targeted compounds through an effective pipeline. Integrated analysis of highthroughput molecular biological data using the R2 bioinformatic platform (http://r2.amc.nl) allowed identification of neuroblastoma driving oncogenes as BCL2, BIRC5, CDK4, CDK2, DNA-PK, EZH2, LIN28B and FOXR1 (2). Compounds against several of these target genes were further validated in vitro and in vivo. We conclude that a personalized treatment approach in pediatric cancer should include a broad biological typing.

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