[New insights into the genetic basis of neuroblastoma]. / Nieuwe inzichten in de genetische basis van neuroblastoom.

Neuroblastoma (NB) is, next to acute lymphoblastic leukaemia, brain tumours and lymphoma the most frequent paediatric tumour (8-10%). Our research group aims to contribute to the unravelling of the genetic basis of NB. Insight into the genes and signalling pathways involved in tumour formation and development can represent an essential step towards the development of more efficient molecular targeted therapies. A first part of our research work was devoted to the analysis of genomic alterations in NB. By means of a new highly sensitive method for detecting gains and losses of chromosomal segments, we recognised three major prognostic relevant genomic subtypes of NB. In addition smaller subgroups with deviating genomic patterns were detected. In addition, this work yielded important information regarding delineation of critical regions of gain and loss in NB which should facilitate further selection of candidate oncogenes or tumour suppressor genes. A second important part of our work focussed on the gene expression profiling of NB precursor cells. We were able as the first to isolate these cells and determine their transcriptome, a finding of fundamental importance for future expression studies in NB. Another study focussed on the identification of MYCN transcriptional target genes. Gene expression analyses of model systems developed in our lab and of a large panel of cell lines and tumours allowed us to subtract a list of candidate genes which are now under further study. Finally, we initiated research towards the understanding of the role of methylation in NB oncogenesis. From this, we were able to create a list of potentially relevant methylated genes in NB. From the above it is clear that our team has made important contributions to the understanding of the complex biology and clinical behaviour of NB. Also, a broad technically innovative research platform has been developed which will allow us to dissect NB genetics with greater speed and accuracy.

Genome wide measurement of DNA copy number changes in neuroblastoma: dissecting amplicons and mapping losses, gains and breakpoints.

In the past few years high throughput methods for assessment of DNA copy number alterations have witnessed rapid progress. Both 'in house' developed BAC, cDNA, oligonucleotide and commercial arrays are now available and widely applied in the study of the human genome, particularly in the context of disease. Cancer cells are known to exhibit DNA losses, gains and amplifications affecting tumor suppressor genes and proto-oncogenes. Moreover, these patterns of genomic imbalances may be associated with particular tumor types or subtypes and may have prognostic value. Here we summarize recent array CGH findings in neuroblastoma, a pediatric tumor of the sympathetic nervous system. A total of 176 primary tumors and 53 cell lines have been analyzed on different platforms. Through these studies the genomic content and boundaries of deletions, gains and amplifications were characterized with unprecedented accuracy. Furthermore, in conjunction with cytogenetic findings, array CGH allows the mapping of breakpoints of unbalanced translocations at a very high resolution.