Cross-study analysis of gene expression data for intermediate neuroblastoma identifies two biological subtypes

Abstract

Background: Neuroblastoma patients show heterogeneous clinical courses ranging from life-threatening progression to spontaneous regression. Recently, gene expression profiles of neuroblastoma tumours were associated with clinically different phenotypes. However, such data is still rare for important patient subgroups, such as patients with MYCN non-amplified advanced stage disease. Prediction of the individual course of disease and optimal therapy selection in this cohort is challenging. Additional research effort is needed to describe the patterns of gene expression in this cohort and to identify reliable prognostic markers for this subset of patients.

Methods: We combined gene expression data from two studies in a meta-analysis in order to investigate differences in gene expression of advanced stage (3 or 4) tumours without MYCN amplification that show contrasting outcomes (alive or dead) at five years after initial diagnosis. In addition, a predictive model for outcome was generated. Gene expression profiles from 66 patients were included from two studies using different microarray platforms.

Results: In the combined data set, 72 genes were identified as differentially expressed by meta-analysis at a false discovery rate (FDR) of 8.33%. Meta-analysis detected 34 differentially expressed genes that were not found as significant in either single study. Outcome prediction based on data of both studies resulted in a predictive accuracy of 77%. Moreover, the genes that were differentially expressed in subgroups of advanced stage patients without MYCN amplification accurately separated MYCN amplified tumours from low stage tumours without MYCN amplification.

Conclusion: Our findings support the hypothesis that neuroblastoma consists of two biologically distinct subgroups that differ by characteristic gene expression patterns, which are associated with divergent clinical outcome.

Figure 1

Hierarchical clustering of the expression data for the significant genes in advanced stage MYCN non-amplified tumors. (A) Oligonucleotide data. (B) cDNA data. The colored bars at the top of the figure denote the values of the following clinical variables: Status: black – unfavourable outcome, grey – favourable outcome; Age (at diagnosis): black – older than one year, grey – younger than one year; Stage: black – INSS stage 4, grey – INSS stage 3.

Figure 2

Hierarchical clustering of the expression data for the significant genes in advanced stage MYCN amplified tumors versus low stage non-amplified tumors. (A) Oligonucleotide data. (B) cDNA data. The colored bars at the top of the figure denote the values of the following clinical variables: Status: black – unfavourable outcome, grey – favourable outcome; Age (at diagnosis): black – older than one year, grey – younger than one year.