Background: Neuroblastoma is a biologically and genetically heterogeneous tumor and demonstrates favorable or unfavorable outcomes. However, the number of subgroups in neuroblastoma and natural history of each subgroup remain unclear. In Japan, nation-wide neuroblasotma mass-screening project had been performed on 6-month-old babies for approximately 20 years that might have detected almost all neuroblastomas including regressing/ maturing tumors developed in this period. We surveyed more than 3,600 neuroblasotma cases including approximately 2,000 MS detecting cases. Genome-wide single nucleotide polymorphism (SNP) arrays could frequently identify chromosomal aberrations and allelic imbalances including 1p and 11q loss and MYCN amplification in neuroblastoma. In this study, we examined chromosome aberration patterns in the representative cases using genome-wide SNP array and compared with the clinical courses.

Methods: Genomic DNA was extracted from 198 neuroblastoma samples. SNP array was used to determine genome-wide aberrations. Chromosome aberrations were confirmed by BAC array and FISH examination. Expression profiles of these tumors were also examined using whole genome oligonucleotide microarrays.

Results: We broadly classified the chromosome aberrations in neuroblastoma into four types: whole gain/loss type, partial gain/loss type, MYCN amplified type, and silent type without large alterations. In 32 MYCN amplified type tumors, 26 showed more than one amplicons located in 2p22-25 and 28 showed large 1p deletion including 1p 32-36. Almost all MYCN amplified tumors showed poor prognosis. In 52 partial gain/loss type tumors, most tumors with 2p gain or 11q unbalanced loss showed poor prognosis, while 14 tumors with 7q and/or 16q gains did not. The gain lesions in 2p were various while almost all 11q unbalanced loss occurred at 11q13. Unbalanced gain in 17q was detected in partial gain/loss type and MYCN amplified type tumors. In 49 silent type tumors without large aberrations, 16 unfavorable tumors had small deletions and/or gains in 1p, 2p, 3p, 11q, and/or 17q, while the remaining 33 favorable cases did not. The expression profiles of the unfavorable tumors revealed high expression of several genes (DDX1, NAG, NME1, MAC30) located in these 2p and 17 q loci and low expression of several genes in 11q.

Conclusions: Genome-wide genetic analysis classified neuroblastoma into four types, which are useful to predict the outcome of patients. In the silent type and partial gain/loss type, differential regulation of several genes at altered loci was observed only in unfavorable tumors that would serve for prediction of the outcome of the patients. These data provided important candidates of indicators for risk assessment and of therapeutic targets for unfavorable neuroblastoma.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA