Identification of genes that are regulated transcriptionally by Myc in childhood tumors

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Abstract
BACKGROUND Amplification of the N-myc oncogene is associated with adverse outcomes in the common childhood tumor, neuroblastoma. Because the transforming properties of Myc are related to its ability to modulate gene expression, the authors used cDNA microarrays to identify potential Myc target genes. METHODS Expression levels of 4608 genes were analyzed in a series of neuroblastoma cell lines. Identical analyses were performed in a panel of medulloblastoma cell lines to identify c-Myc targets and to determine the extent to which N-Myc targets and c-Myc targets were shared. Comparisons were made between cell lines with high levels versus low levels of Myc protein expression. RESULTS Array analyses yielded 121 genes with increased expression levels (≥ 1.65-fold) and 9 genes with decreased expression levels in N-Myc-expressing versus nonexpressing cell lines. Many of these were newly identified targets of biologic interest. Fifty percent of the N-Myc targets (60 of 121) were mutual c-Myc targets. A significant correlation between the level of N-myc and selected target gene expression was demonstrated independently in 27 neuroblastoma tumor samples and in an N-myc-inducible cell line system. CONCLUSIONS A number of diverse pathways are modulated by N-Myc in neuroblastoma. Although, overall, there was significant correlation between myc and target transcript expression among cohorts of tumors, great variability in levels of target expression was seen among individual tumor samples, and this biologic heterogeneity in the levels of target gene expression may offer insight into differences in the clinical behavior of neuroblastoma and may prove to be of prognostic significance in the future. Cancer 2003;98:841–53. © 2003 American Cancer Society. DOI 10.1002/cncr.11584