Tissue-dependent and tissue-independent gene expression changes in metastatic colon cancer

Abstract

20014 Background: Changes in gene expression that occur during cellular transformation and establishment of metastases provide valuable information that may help determine prognosis and direct treatment. We have obtained gene expression profiles from primary colon tumors and metastases to the liver (V), lung (L), and peritoneum (P). Methods: Ten cases, with matched controls, were profiled for the expression of >18,000 human transcripts using Affymetrix U133A chips. Data were filtered using GeneSifter analysis software to identify genes with 2-fold or greater differences in expression relative to the control group. Gene expression levels for primary colon samples were compared to normal colon while metastatic tissues were compared to primary colon samples. Differentially regulated genes were then associated with KEGG pathways for additional analysis. Results: Relative to normal colon samples, primary colon samples displayed high positive z-score values for genes involved in nitrogen and sulfur metabolism (7.30 and 8.10, respectively). Expression level changes for individual genes in each cluster were statistically significant (e.g. p = 0.014 for carbonic anhydrase I in the nitrogen metabolism cluster). Metastatic tissue from liver, lung and peritoneum all displayed substantially decreased expression for genes involved in butanoate and propanoate metabolism, valine, leucine and isoleucine degradation, and moderately decreased expression for genes involved in JAK-STAT signaling. For example, L-3-hydroxyacyl-Coenzyme A dehydrogenase (short chain), a gene involved in both butanoate metabolism and valine, leucine and isoleucine degradation, was down-regulated in tissue from all three metastatic sites relative to primary colon tumor tissue [p = 0.024 (V), p = 0.022 (L), p = 0.005 (P)]. In addition, genes involved in phosphatidylinositol signaling were down-regulated in liver metastases but not in lung or peritoneal metastatic tissue. Conclusions: These results demonstrate that changes in expression levels for genes involved in basic metabolism and cell signaling occur during the course of metastasis. The changes that occur during development of the metastatic phenotype can be independent of, or specific to, the site of metastasis. No significant financial relationships to disclose.