[The neuroblastoma, "enfant terrible" among pediatric tumors]

Neuroblastoma belongs to the group of small blue round cell tumors and originates in precursor cells of the sympathetic neural tissue. This tumor occurs at the pediatric age and has fascinated and intrigued both clinicians and researchers because of its variable and often unpredictable clinical behaviour. Indeed, the clinical outcome of neuroblastoma patients not only depends on the clinical extension of the disease, but also on other factors including age at diagnosis, presence or absence in the tumor cells of molecular and biological characteristics with prognostic value (e.g. amplification of the oncogene MYCN, frequently associated with chromosome 1p-deletion is predictive for poor survival chance). In 1983 an abdominal stage 3 neuroblastoma was diagnosed in a 9-months old boy. He died of the disease 3 years later. Karyotyping studies in this patient revealed a constitutional chromosome translocation t(1;17) with a breakpoint involving the terminal part of the chromosome 1p arm. We hypothesized that this patient was predisposed to the development of neuroblastoma because he carried in all his somatic cells a chromosomal abnormality involving the region frequently deleted in neuroblastoma tumor cells. We assumed that the chromosomal translocation breakpoints might indicate the regions harbouring genes involved in neuroblastoma development. A somatic cell fusion experiment was performed between the patient's fibroblasts (the only remaining source of patient material) and a fast growing Chinese hamster ovary cell line to assure the possibilities to perform further research. These somatic cell hybrids indeed contained the human translocation chromosomes. Further characterization of the translocation breakpoints by FISH (fluorescent in situ hybridisation) resulted in the identification of NPPA (formerly PND, the gene for pronatriodilatine) and A12M2 (an adenovirus integration site) as flanking markers for the 1p breakpoint. The 17q breakpoint was located between the NF1 (neurofibromatosis 1) gene and the SCYA7 (harboring the gene encoding the monocyte chemotactic protein-3). Starting from these markers chromosome walking experiments furthered the characterization of the chromosomal breakpoint regions and enabled to identify breakpoint overlapping cosmids. Sequence analysis of these markers is ongoing and will reveal if the breakpoint regions indeed harbour a gene involved in neuroblastoma development.