MYCN-non-amplified metastatic neuroblastoma with good prognosis and spontaneous regression: A molecular portrait of stage 4S

Abstract 

Stage 4 neuroblastoma (NB) are heterogeneous regarding their clinical presentations and behavior. Indeed infants (stage 4S and non-stage 4S of age <365days at diagnosis) show regression contrasting with progression in children (>365days). Our study aimed at: (i) identifying age-based genomic and gene expression profiles of stage 4 NB supporting this clinical stratification; and (ii) finding a stage 4S NB signature. Differential genome and transcriptome analyses of a learning set of MYCN-non amplified stage 4 NB tumors at diagnosis (n=29 tumors including 12 stage 4S) were performed using 1Mb BAC microarrays and Agilent 22K probes oligo-microarrays. mRNA chips data following filtering yielded informative genes before supervised hierarchical clustering to identify relationship among tumor samples. After confirmation by quantitative RT-PCR, a stage 4S NB's gene cluster was obtained and submitted to a validation set (n=22 tumors). Genomic abnormalities of infant's tumors (whole chromosomes gains or loss) differ radically from that of children (intra-chromosomal rearrangements) but could not discriminate infants with 4S from those without this presentation. In contrast, differential gene expression by looking at both individual genes and whole biological pathways leads to a molecular stage 4S NB portrait which provides new biological clues about this fascinating entity.

Keywords: Metastatic neuroblastoma, Stage 4S, Molecular signature

Abbreviations: NB, neuroblastoma, infants, patients <365days of age at diagnosis of NB, children, patients >365days of age at diagnosis, stage 4S NB, metastatic NB of neonate or infant with a very special clinical presentation (small primary and hepatic, skin nodules, bone marrow involvement without bone metastasis, [1yr⁻] stage 4 NB, metastatic NB of infant without stage 4S NB clinical criteria;, [1yr⁺] stage 4 NB, metastatic NB of children, Q-RT PCR, quantitative reverse transcribed PCR, S.B.I.M.E., Searching Biological Interpretation of Microarrays Experiments’ software, DI, DNA index