Phox2b

4p12

Regulation of transcription, DNA dependent, neurogenesis, development

tive to non-neoplastic tissues (including fetal and mature brain tissue, spinal cord, bone marrow, liver, lung, and kidney). Many of the functionally annotated genes that are highly over-expressed in high-risk NB are believed to play a role in cell growth, development, differentiation, and histogenesis (unpublished data). A significant number are specifically annotated as playing a role in neurogenesis (Table 9.1). It is also interesting that a high proportion (about 38 % of the most strongly differentially expressed genes) of these NB-specific genes are expected to function in some aspect of transcription and a significant number (about 19%) are believed to be part of signaling pathways. Many of these genes are highly specific for NB and may enhance our ability for accurate diagnosis and identification of therapeutic targets.

From an unsupervised analysis (average linkage hierarchical clustering) of gene expression in NB, it is clear that differentiation is a key factor reflected in the profiles (Fig. 9.2). Cell lines composed of relatively pure populations of poorly differentiated neuroblastic cells are relatively distinct and aligned with a subset of stroma-poor NB that are similarly composed of poorly differentiated neuroblasts. Likewise, ganglioneuromas and NB containing a large component of Schwannian cells (stroma-rich) have expression profiles that are distinct from stroma-poor tumors. This is a reflection of the very different expression patterns of Schwann cells and neuroblasts. Stroma-poor (neuro-blast-rich) tumors are characterized by a greater level of expression for genes associated with DNA replication and cell division, and molecules regulating early

Figure 9.2

Graphic display of a hierarchical cluster analysis of NB gene expression.The dendrogram represents relationship between samples.Branch length is based on 1 - Pearson's correlation coefficient between the samples of that branch. Columns are individual samples and rows represent an individual gene.Sample types are indicated at the top of each column just below the dendrogram. Expression levels are pseudocoloredred to indicate transcript levels above the median for that gene across all samples and green below the median. Color saturation is proportional to the magnitude of expression

Table 9.2. General biological function most commonly assigned to genes correlating with differentiation in neuroblastoma

General biological function

Differentially expressed genes over-expressed in stroma-poor NB (%)a

Differentially expressed genes over-expressed in stroma-rich NB (%)a

Cell cycle, DNA replication and repair

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