Identification of early changes associated with the development of preneoplastic conditions and especially those that are responsible for their progression to invasive cancer would provide important clue on early cancer development and could aid in the development of novel markers for early identification of occult neoplasia. We have used a whole-genome approach to identify target loci on individual chromosomes, focusing our effort on those chromosomal regions that are involved early in the process of development of human urinary bladder neoplasia. From these data we selected several target loci for further characterization and development of diagnostically relevant probes for early cancer detection. We anticipate that this proposal will fill up an important gap in our knowledge on early occult events of human urinary bladder neoplasia. The overall goal of this project is to characterize target tumor suppressor gene loci on chromosomes 4, 8, 11 and 17, as well as minimally amplified regions on the chromosome 3q24-26 amplicon. On the basis of our strong preliminary data, we hypothesize that putative tumor suppressor and dominantly activated genes in these loci are involved in the development of early phases of urinary bladder neoplasia and that some of them play a role in the progression of preneoplastic intraurothelial conditions to invasive bladder cancer. From these loci, we propose to develop fluorescent in situ hybridization (FISH) and hypervariable DNA marker assays for early detection of occult urinary bladder neoplasia. The core preliminary data for this proposal are the result of the application of our genome-wide model of urinary bladder cancer progression from occult in situ preneoplastic conditions to invasive cancer. Using our whole organ histologic and genetic mapping method, we identified over 30 putative tumor suppressor gene foci involved in the development and progression of urinary bladder cancer. The most promising and putative tumor suppressor gene loci and the target amplicon were selected for further characterization, the development of markers to detect early occult urinary bladder neoplasia and its aggressive variants, and the testing of these markers under realistic clinical conditions. This project will provide two products of basic research and practical importance: (1) A public database consisting of all tested foci and the characterization of their minimally deleted or amplified regions as well as their transcriptionally active sequences; (2) A diagnostically relevant panel of FISH and hypervariable DNA markers for early detection of bladder cancer. As all transforming and tumor suppressor genes are relevant for more than one cancer type, these data will have a significant impact on our understanding of multistep human carcinogenesis in general and will serve as a paradigm for the development of markers and diagnostic strategies for early detection of other types of cancer.
