This proposal is based on a model of urothelial cancer in which tumors develop along two histologic and molecular pathways: Lowgrade superficialtumors (pTaGi), which have frequent recurrences but rarely progress to muscle invasion;and high grade tumors which present either with early invasion into the lamina propria (pTiGs), or with more extensive muscle invasion (pT2-T4).We and others have identified a number of candidate genes and chromosomal alterations which are associated with these different pathways, and with clinical outcome.We hypothesize that overall genomicinstability and specificgenomic alterations are associated with environmental risk factors and with patient outcome. The overall design ofthis study is to characterize over 800 bladder tumors by array CGHandgene-specific analyses to define associations of molecular alterations with environmental exposures and with clinical outcome. These tumors have alreadybeen collected with associated data by our Spanish and NCI collabor- ators. Wewill validate associations between genomicalterations and patient outcome on a separate setof tumors collected as part ofthe International Bladder Tumor Marker Group. Specifically,we propose to:
Aim i. Identify molecular alterations associated with environmental exposures in bladder cancers from the Spanish/NCI EPICURO Study. lA) Characterizemolecular and genomic alterations in 250 pTa/Gi and 250 pT2-pT4/Gs tumors. Fraction genome altered and loci of specificalteration including DNA amplifications and homozygousdeletions will be studied by array-CGH,expression signature by quantitative RT-PCR, and sequencing will identify mutations in pss and FGFRs. iB) Identify associations between environmental exposures and genomic/geneticalterations in the pTa/Gi and pT2-pT4 tumors applying aCase-Case- Control study design. Exposures to be tested willbe tobacco smoke and trihalomethanes, which showed the strongest effects in the Case-Control study.
Aim 2. Identify genomic and gene-specific alterations associated with patient outcome in both pTa and pT2-T4 tumor groups from the EPICURO study. Array-basedCGH and gene-specificexpression analyses will be tested to confirmgenetic signatures predictive of patient outcome.
Aims. Asecond cohort of 300 pTs muscle invasive tumors will be used to validate the predictive signatures tested in Aim 2. These tumors are being collected as part of International Bladder TumorMarker Study to evaluatepredictive markers in urothelial cancer. Relevance: Bladdercancer is a major cause of morbidity and mortality in the United States and internationally and is among the top 5 in cancer incidence. This study will identify whether environmental exposures lead to geneticalterations in tumors, and whether such alterations predict patient outcome.
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