Abstract
BackgroundNeuroblastoma (NB) tumours have the highest incidence of spontaneous remission, especially among the stage 4s NB subgroup affecting infants. Clinical distinction of stage 4s from lethal stage 4 can be difficult, but critical for therapeutic decisions. The aim of this study was to investigate chromosomal alterations and differential gene expression amongst infant disseminated NB subgroups.MethodsThirty-five NB tumours from patients diagnosed at < 18 months (25 stage 4 and 10 stage 4s), were evaluated by allelic and gene expression analyses.ResultsAll stage 4s patients underwent spontaneous remission, only 48% stage 4 patients survived despite combined modality therapy. Stage 4 tumours were 90% near-diploid/tetraploid, 44% MYCN amplified, 77% had 1p LOH (50% 1p36), 23% 11q and/or 14q LOH (27%) and 47% had 17q gain. Stage 4s were 90% near-triploid, none MYCN amplified and LOH was restricted to 11q. Initial comparison analyses between stage 4s and 4 < 12 months tumours revealed distinct gene expression profiles. A significant portion of genes mapped to chromosome 1 (P < 0.0001), 90% with higher expression in stage 4s, and chromosome 11 (P = 0.0054), 91% with higher expression in stage 4. Less definite expression profiles were observed between stage 4s and 4 < 18m, yet, association with chromosomes 1 (P < 0.0001) and 11 (P = 0.005) was maintained. Distinct gene expression profiles but no significant association with specific chromosomal region localization was observed between stage 4s and stage 4 < 18 months without MYCN amplification.ConclusionSpecific chromosomal aberrations are associated with distinct gene expression profiles which characterize spontaneously regressing or aggressive infant NB, providing the biological basis for the distinct clinical behaviour.
Highlights
Neuroblastoma (NB) tumours have the highest incidence of spontaneous remission, especially among the stage 4s NB subgroup affecting infants
According to our preliminary results, distinct chromosomal aberrations may be reflected in gene expression profiles associated with spontaneously regressing or aggressive infant NB, and with the distinct clinical behaviour
Our report identifies a distinct gene expression profile between infant stage 4 and 4s NB and regional chromosomal expression patterns correlating with specific genomic abnormalities for each subgroup of tumours
Summary
Neuroblastoma (NB) tumours have the highest incidence of spontaneous remission, especially among the stage 4s NB subgroup affecting infants. In 1971, a special and rare subgroup of metastatic NB affecting very young infants and characterized by a unique pattern of dissemination and a high incidence of spontaneous regression was described [1]. This subgroup, designated stage 4s (s for special), has been recognized as a distinct clinical entity in all subsequent classifications of NB [2]. Clinical distinction between 4s and 4 can be difficult, especially among patients with 1) distant but no bony metastases, 2) distant MIBG positivity, 3)
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