438 IDENTIFICATION OF SIGNIFICANT PATHWAY ALTERATIONS IN METASTATIC RENAL CELL CARCINOMA USING GENE SET ENRICHMENT ANALYSIS (GSEA) – A TWO-CENTER STUDY

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2012438 IDENTIFICATION OF SIGNIFICANT PATHWAY ALTERATIONS IN METASTATIC RENAL CELL CARCINOMA USING GENE SET ENRICHMENT ANALYSIS (GSEA) – A TWO-CENTER STUDY Alexander Buchner, Matthias Maruschke, Dirk Koczan, Christian Stief, and Oliver Hakenberg Alexander BuchnerAlexander Buchner Munich, Germany More articles by this author , Matthias MaruschkeMatthias Maruschke Rostock, Germany More articles by this author , Dirk KoczanDirk Koczan Rostock, Germany More articles by this author , Christian StiefChristian Stief Munich, Germany More articles by this author , and Oliver HakenbergOliver Hakenberg Rostock, Germany More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.505AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES There is very limited knowledge about biological alterations that occur in metastases of renal cell carcinoma (RCC) patients. The identification of changes in pathways during malignant transformation and progression of RCC is a crucial step for the development of new and specific targeted therapies. For this purpose, we used gene expression data from RCC patients that underwent tumor surgery (primary or metastatic RCC) in two university hospitals and we utilized a new pathway analysis method that is able to detect even subtle changes in the expression of co-regulated or co-localized genes. METHODS Whole genome expression profiling was done on 32 snap-frozen samples of clear-cell RCC metastases, 28 primary tumors (14x grade G1, 14x grade G3), and 14 samples of normal kidney tissue using oligonucleotide microarrays (GeneChip HG U133 Plus 2.0, Affymetrix). These data were analyzed with the GSEA (gene set enrichment analysis) method that uses a database of several thousand predefined sets of genes. Genes in the same set share pathway or localization, and GSEA is able to detect even small, but significant expression changes in these functionally connected genes that cannot be revealed by gene-by-gene comparisons. RESULTS There were 95 gene sets with significant upregulation in metastases compared to normal kidney tissue (p<0.01), and 77 gene sets with significant downregulation (p<0.01), respectively. 20 gene sets showed significant upregulation in metastases in comparison to poorly differentiated primary tumors (G3; p<0.01), and 149 gene sets were significantly downregulated (p<0.01), respectively. Numerous housekeeping genes were significantly downregulated in RCC metastases in comparison to G3 primary RCC, and upregulation of several oncogenic pathways could be demonstrated in metastases that were previously not known in RCC. There were also significant changes in genes that are involved in cell mobility, and in genes that regulate cellular membrane transports and homeostasis. Comparison of RCC metastases with normal renal tissue showed significant changes of genes involved in mitosis, cell motility, angiogenesis, lipid metabolism, intercellular adhesion and various signaling pathways. CONCLUSIONS The combination of expression profiling of precisely defined tissue samples with the GSEA pathway analysis method provides new and detailed insights in alterations that occur in RCC during malignant transformation and progression. These data can help to develop new and specifically targeted RCC therapies. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e179-e180 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alexander Buchner Munich, Germany More articles by this author Matthias Maruschke Rostock, Germany More articles by this author Dirk Koczan Rostock, Germany More articles by this author Christian Stief Munich, Germany More articles by this author Oliver Hakenberg Rostock, Germany More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...