(based on the applicant's narrative) The applicants propose to apply molecular cytometric techniques to identify and evaluate genetic markers for cancer of the urinary bladder. Their strategy for studying genetic markers is based on the generally accepted notion that aberrations at several loci arerequired for pathogenesis, growth and progression of bladder cancer and that advanced tumors carry the greatest number of such aberrations. Studies will focus on genetic events already implicated in bladder cancer or other solid tumors. The investigators plan to emphasize utilization of fluorescence in situ hybridization and computer assisted fluorescence microscopy to identify, in individual cells, genetic markers that are associated with bladder cancer. A key aspect of their approach is that it is based onexamining individual cells; thus it permits analysis of a small genetically defined tumor population.
The specific aims are: 1) identification of potential markers. They plan to identify genetic markers that show a high prevalence of aberrations in invasive bladder cancers. a) FISH will be used to evaluate aberrations (deletions or amplifications) of specific genes already implicated in bladder cancer and to define more precisely other regions of the genome that are important in bladder cancer progression. 2) evaluation of genetic and other markers. The investigators plan to characterize the distribution of aberrations of candidate genetic markers in sets of selected tumors. Clinical end points will be used to validatethe ability of these markers to a) identify superficial tumors (TIS, Ta, T1) that will recur and/or progress to invasion; b) identify invasive tumors (T2, T3, T4) that will metastasize; c) detect tumor cells exfoliated into urine or bladder washings; and d) identify genetic relationships among multiple tumors within individual patients. Genetic markers also will be comparedto known indicators of tumor behavior, including tumor stage, tumor grade, cellular proliferation, and other phenotypic markers. Pilot studies will utilize the applicants' material, but it is anticipated that validation of predictive power will require many tumors analyzed through the Bladder Cancer Marker Network. 3) Collaborative Bladder Cancer Marker Network responsibilities. The investigators plan to continue ongoing Network responsibilities: FISH analysis of genetic markers, flow analysis for DNA content and S phase, coordination of studies of cellular proliferation, development and supervision of the network database, and shared design, execution, and analysis of new network experiments. This application is in response to the requirements of the Bladder Cancer Marker RFA CA-91-09; it is based on the applicants' current experience applying FISH and other cytometric markers. The investigators anticipate that it should lead to improved detection and management of urinary bladder cancer.
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