Non amplified-MYCN stage 4 neuroblastoma: A genomic signature associated with good prognosis and spontaneous regression.

2955 Background Clinical classification of non amplified-MYCN infantile stage 4 neuroblastoma (NB) recognizes 3 distinct patterns of disease and associated prognosis. These include babies under 12 months of age of two good prognosis subtypes ,i.e., NB stage 4S (see text for definition) and stage 4 NB without this presentation ([1yr - ]), and children older than 12 months ([1yr + ]) with a very poor outcome. To date, no genetic criteria permitting such sub-classification of stage 4 NB in infants have been identified. Methods MYCN-non amplified undifferentiated NB tumors series included 12 [4S], 8 [1yr - ]stage 4, and 9 [1yr + ] stage 4. 1Mb BAC microarrays surveyed the genomic anomalies. Agilent 22k probes oligomicroarrays analyzed the differential transcriptome profiles of the tumor sets, using a combined methodological approach. Firstly, mRNA chips data were subjected to filtering to yield informative genes before unsupervised hierarchical clustering to identify relationship among tumor samples. Identified gene clusters were confirmed by TaqMan quantitative RT-PCR. Secondly, the chips data were also explored directly, on the basis of p-values derived from variance analysis and robustness tests using a new dedicated software that allows sorting out ontologies, functional pathways and interaction networks. Results Chromosomal landscape of infants tumors (whole chromosomes gains or loss) differ radically from that of olderchildren (partial chromosome gains or loss). Tumor expression profiling depicts specific biological functions and pathways for each clinical stage 4 type with regards to transcription factors expression, mitochondrial activity, metabolisms and immune response. Conclusion Chromosomal instability in stage 4S tumors associated with a neuro-developmental and proliferative cell phenotype (cell growth, mitochondrial activity, lipid metabolism up-regulations) may likely trigger a genotoxic stress. This could result in cell cycle arrest and a subsequent inflammatory/immune response. Such a multifactorial biological process might explain the strikingly low malignant potential of stage 4S NB.