MOLECULAR PROFILING OF UROTHELIAL CARCINOMA

Abstract: The general aim of this thesis was to molecularly characterize urothelial carcinoma (UC) at the transcriptional level using gene expression microarrays to improve the classification and pathogenetic understanding of this disease. In the first two studies (Articles I and II), gene expression profiling was used to study dysregulated transcriptional networks in a large cohort of UCs. We also investigated possible associations between the expression profiles and tumor stage/grade, or mutation status of FGFR3/TP53 and LOH for chromosome 9. It was shown that the mutational status of FGFR3 and TP53 correlated with large transcriptional differences, thus indicating for two different molecular pathways of UC development. Furthermore, we found gene signatures associated with specific biological functions that correlated with molecular and histological subgroups. Finally, a high expression of MHC-class I related genes in patients with muscle-invasive tumors provided independent prognostic information for lymph-node status and overall survival. In the third study (Article III), the genetic relation between syn- or metachronous tumors was explored, revealing that the expression profile is remarkably stable in tumors collected from the same patient, despite large genomic differences. This suggests that the formation of a fixed expression profile may be an early event in the development of UC. In the final study (Article IV), we combined high-resolution BAC arrays with gene expression profiling and could show that E2F3, CDKAL1, and SOX4 in 6p22, and YWHA (14-3-3) gene family members in 8q22 and 2p25, respectively, are major target oncogenes important for high grade disease.