Gene Expression Associated with Clinically Relevant Subtypes of NB

Supervised approaches to data analysis allow the identification of genes that are differentially expressed in the biologically and clinically distinct subsets of NB tumors. For example, comparison of stro-ma-poor stage-4 NB with known bone metastasis to stroma-poor LR NB that were cured with surgery alone demonstrated a number of differentially expressed genes that are known to participate in cell cycle regulation, DNA replication, mitosis, and cell division. These genes reflect the striking differences in cell replication known to exist between these two groups and most are over-expressed in stage-4 tumors. Other differentially expressed genes encode proteins with a wide variety of proposed biological functions; however, it is of interest that some of the genes over-expressed in LR NB included several with anti-apoptotic activity (OPTN, TIAF1, PRKCZ) and some that play a role in neurogenesis (PAFAH1B1, PMP22; Li et al. 1998; Chang et al. 1998; Rust et al. 2000; Sweeney et al. 2000; Wulf et al. 1999).

Other studies investigating the gene expression patterns of individual NB risk groups have recently been published. Sequence analysis of cDNA libraries from NB defined as favorable (single-copy MYCN, high NTRK1 expression) or unfavorable (amplified MYCN and low NTRK1) revealed a large number of genes that were relatively over-expressed in the favorable tumors (Ohira et al. 2003), including genes that are believed to play a role in cell signaling, transcription, protein synthesis, and cell homeostasis. Few genes were identified that were over-expressed in unfavorable NB.

Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Activation of telomerase has been implicated in cell immortalization and cancer cell pathogenesis and is associated with outcome in NB (Choi et al. 2000). Comparison of NB with high or low telomerase activity, using a cDNA array corresponding to genes expressed in the human fetal brain, identified 63 genes over-expressed in tumors with high telomerase activity and 46 with low activity (Hiyama et al. 2003). The over-expressed genes in tumors with high telomerase activity included those involved in cell cycle, apoptosis escape, protein synthesis, and transcription. Those over-expressed in tumors with low-level telomerase included neural transmitters and several receptors associated with neural or neuroendocrine function. These genes again reflect the biology of distinct NB risk groups with active cell replication in high-risk groups and increased degrees of neural differentiation in low-risk tumors.

These preliminary results suggest that clinically relevant NB subgroups have distinct molecular profiles and that characterization of individual molecules will lead to a better understanding of NB biology and provide the means for molecular classification that may be used in conjunction with traditional clinical features for improved patient care. It is intriguing to speculate that the clinical behavior of a NB may one day be more accurately predicted by expression analysis than by the clinical and biological features that are currently utilized for patient risk stratification and treatment.

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