Through Gene Expression Analysis

Gene expression profiling is a powerful technique to discover previously unrecognized tumor subtypes and distinct molecular phenotypes. For example, a search of SAGE libraries for genes related to development identified DLK1 as dramatically over-expressed in some NB cell lines (van Limpt et al. 2000). Further study suggested that DLK1 over-expression was not due to amplification or mutation but was associated with chromaffin differentiation (van Limpt et al. 2003). Data from our own studies suggest that high levels of DLK1 expression is more common in a subset of high-risk NB (unpublished data).

Analysis of genome-wide expression data for NB samples based on oligonucleotide arrays revealed a subset with over-expression of several contiguous genes located at 12q13-15 (W. Su et al., 2004). Regional over-expression suggests a chromosomal amplification event and consistently expressed genes represent candidate oncogenes. About 5% of NB tumors demonstrate 12q gene over-expression. Positional expression mapping identified the narrowest region of overlap containing 21 genes, with 11 genes over-expressed by all cases. In cases with high levels of expression for genes at 12q, three- to more that tenfold increase in 12q gene copy number was detected by fluorescent in situ hybridization. Amplification of 12q has been identified in a large variety of other cancer types. The 12q expressed genes in NB mapped to a site similar to the complex amplicon reported in sarcomas and gliomas and identify critical genes and pathways affected by 12q gene amplification (Fig. 9.4). This use of positional gene expression mapping provides a means to efficiently filter and select genes within altered chromosomal regions that are prime candidates to contribute to neoplastic development. Importantly, the data described here suggest that gene expression analysis can identify molecular markers that segregate with biological pheno-type and molecular classification of NB.

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