Oncogenomic transcriptional hotspots in Barretts adenocarcinomas

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AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 2981 Serial analysis of gene expression (SAGE) provides quantitative and comprehensive expression profiling in a given cell population. In our efforts to define gene expression alterations in Barrett’s related adenocarcinomas and to look for correlations in chromosomal location, we produced eight SAGE libraries from dissected neoplastic and normal epithelia. Sequence analyses of 20,000 clones produced a total of 457,894 expressed tags with 67,200 unique tags. These tags represent 16,040 known gene symbols. Comparison of normal and tumor library results demonstrated an up-regulation of 242 genes and a down-regulation of 153 genes (two fold change, p<0.05). Ninety-three genes showed five fold or greater change in expression (p≤0.01) in at least two tumor samples as compared to all four normal libraries. In order to identify potential oncogenomic transcriptional hot spots in the Barrett’s genome, we have characterized the cytogenetic location of all altered genes. Interestingly, we found that the distribution of these altered genes was not uniform across the human genome. Overexpressed genes tended to cluster in well defined hotspots located in certain chromosomes. We also found that the number of genetic changes did not correlate with chromosome size. Chromosome 19 had twenty-six overexpressed genes of which eighteen mapped to 19q13. Similarly, thirty-five genes mapped to chromosome 1 of which thirteen mapped to 1q21. Using Gene Ontology, We then assigned each gene to a functional group and found several groups that we believe to be highly relevant to cancer. Examples of the more interesting functional groups are cell cycle regulation, DNA binding and regulation, and cell signaling. SAGE results of five representative genes were then validated using quantitative real time RT PCR on 31 primary tumor samples and 23 normal samples. The results confirmed the over-expression of ANPEP, ECGF1, PP1201, EIF5A1 , and the down-regulation of GKN in primary tumor samples as compared to normal tissues. Interestingly, the expression of GKN1 was absent in normal esophageal mucosa whereas Barrett’s esophagus epithelia had high expression levels of GKN1 that was lost in matching tumor samples. In addition, we performed immunohistochemistry analysis for ANPEP on a tumor tissue array that contained 72 samples. The results demonstrate a high expression level of ANPEP in upper gastrointestinal adenocarcinomas. ANPEP is a secreted protein that may have diagnostic or prognostic significance for Barrett’s progression. Using SAGE analysis we have been able to identify and further validate oncogenomic transcriptional hotspots containing multiple genes of functional importance that show changes in expression and may have clinical significance.

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