Gain of chromosome segment 17q21-qter is an important prognostic factor in children with neuroblastoma.

We propose a new regression model for improved patient outcome prediction, incorporating tumor stage, chromosome 17, and amplification/deletion status. These findings may prove highly valuable with respect to more reliable risk assessment, evaluation of clinical results, and optimization of current treatment protocols.

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Real-time RT-PCR (QRT-PCR) is a sensitive method for the detection of minimal disease (MD) and may improve monitoring of disease status and stratification of patients for therapy. Where tumour-specific mRNAs have not been identified, the selection of which target(s) is(are) optimal for the detection of MD remains a challenge. This reflects the heterogeneity of tumour cells, the stability of mRNAs and low-level of transcription in cells of the normal haemopoietic compartments. The aim of this study was to establish for the first time guidelines for the systematic prioritization of potential markers of MD detected by QRT-PCR prior to evaluation in multicentre prospective clinical outcome studies. We combined microarray analysis, ESTs gene expression profiles, improved probe-sets sequence annotation, and previously described standard operating procedures for QRT-PCR analysis to identify and prioritize potential markers of MD. Using this methodology, we identified 49 potential markers of MD in neuroblastoma (NB), of which 11 were associated with neuronal function. We found that, in addition to TH, Phox2B and DCX mRNA may be useful targets for the detection of MD in children with NB. This same strategy could be exploited to select MD markers of other solid tumours from the large number of potential targets identified by microarray gene expression profiles.

A small number of tumors show no detectable imballances. A second group of tumors presents with gains and losses of whole chromosomes and is found predominantly in prognostically favorable stage 1 and 2 tumors. The remaining groups are characterized by the presence of partial chromosome imbalances, and are found mostly in stage 3, 4, and 4S tumors. The third group shows 17q gain without 11q loss, 1p loss, or MYCN amplification (MNA). The fourth group has 1p deletion or MNA, and finally, a fifth group shows 11q loss without 1p deletion or MNA, and is found mainly in stage 4 tumors. The latter group is significantly associated with losses of 3p, 4p, and 14q.

Overexpression of the human MYCN oncogene driven by a tyrosine hydroxylase promoter causes tumours in transgenic mice that recapitulate the childhood cancer neuroblastoma. To establish an in vitro model to study this process, a series of isogenic cell lines were developed from these MYCN-driven murine tumours. Lines were established from tumours arising in homozygous and hemizygous MYCN transgenic mice. Hemizygous tumours gave rise to cell lines growing only in suspension. Homozygous tumours gave rise to similar suspension lines as well as morphologically distinct substrate-adherent lines characteristic of human S-type neuroblastoma cells. FISH analysis demonstrated selective MYCN transgene amplification in cell lines derived from hemizygous mice. Comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH) analysis confirmed a range of neuroblastoma-associated genetic changes in the various lines, in particular, gain of regions syntenic with human 17q. These isogenic lines together with the transgenic mice thus represent valuable models for investigating the biological characteristics of aggressive neuroblastoma.

These studies highlight the histological similarities between tumours from MYCN transgenic mice and human neuroblastomas, and reaffirm their role as a valuable model to study the biology of aggressive human neuroblastoma.