The goal is to identify and validate tumor markers, which predict the outcome of patients with bladder cancer. Analyses of tumor material will be done to define genetic and expression alterations in each tumor, to associate these alterations with the tumor stage, with other clinical characteristics of the tumor, and with the patient's clinical course. High throughput analyses using genomic slide-based arrays comprised of human BAC genomic probes at 1 mb density, and gene expression arrays comprised of more than 7,000 human cDNA clones, will be applied to human bladder tumor samples. Tumor will be grouped by stage in order to identify correlated sets of genes for each group. These gene sets will then be used for testing of prognostic utility in separate sets of patient samples.
The Specific Aims are:
Aim 1. Genetic Alterations During Bladder Cancer Progression. We will test the hypothesis that pathways of tumor progression are genetically defined. DNA copy number and RNA expression alterations will be identified in groups of tumor according to stage of bladder tumor progression. A. Low Grade Superficial Disease (150 pTa tumors). B. High Grade Superficial Disease (100pT1 tumors and 50 pTis). C. Muscle Invasive Disease (150) tumors will be used to identify patterns of genetic alterations and expression changes according to stage. D. Stromal changes in superficial and invasive cancer: Tumor fibroblasts prepared by collaborators (Drs. Hayward) will be used to define altered gene expression patterns in the tumor stroma (compared to fibroblasts away from the tumor). Candidates genes identified in these studies will then be tested for association with tumor stage.
Aim 2. Genetic Alterations as Predictors of Clinical Outcome. Candidate gene alterations identified in Aim 1 will be tested for association with clinical outcome. A. High risk superficial tumor. We will test the utility of candidate gene markers will be tested in separate patient groups for association with outcome after treatment with intravesicle BCG and Gemcitibine. A. High risk muscle invasive tumors. Molecular markers will be tested in patients with node positive tumors who receive no further treatment, and in separate patient groups, as markers of response to MVAC therapy, and as markers of response to taxanes. C. Validation of Candidate Markers with Tissue Arrays. We will use tissue arrays to validate markers which are identified in Aim 1 and tested in Aims 2A-B.
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