Renal cancer genomic alterations and environmental risk

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DESCRIPTION (provided by applicant): A number of environmental, occupational and life style factors have been associated with renal cell cancer (RCC) incidence. However, the mechanism by which these risk factors cause RCC, presumably acting through alteration of specific genes, is unknown. We hypothesize that specific genomic alterations detected in renal cancers (DNA gain or loss) are associated with renal cancer risk factors. We propose to analyze associations between risk factors and genomic alterations in renal tumors collected as part of the Eastern European Renal Cell Cancer Study (EERCC), being carried out by the National Cancer Institute and the International Association for Research on Cancer (IARC). We hypothesize that specific qenomic alterations in renal cancers (DNA gain or loss) are associated with renal cancer risk factors and with tumor proqression. Our Aims are: The overall design of this study is to characterize over 700 renal tumors by array CGH to define genomic alterations and their associations with clinical variables, and with exposure, and genetic risk factors. 1. Identify genomic alterations associated with tumor stage in conventional (clear cell) renal cancer. Array based CGH will be used to define copy number gains and losses, including DNA amplifications and homozygous deletions, in DNA from 200 conventional RCC grouped according to stage (I-IV). 2. Identify associations of genomic alterations with statistically significant exposure, occupational, and genetic risk factors defined using this IARC case-control cohort of renal cancer patients. 500 additional tumors will be characterized by array CGH beyond those studied in Aim 1. Patients will be selected based on their exposure history, to generate the most power for analysis (enriching for highest exposure groups). Risk factors to be considered include smoking, occupational, and environmental exposures (trichloroethylene, polycyclic aromatic hydrocarbons, petroleum products, asbestos, and heavy metals) and factors that alter renal function (obesity and hypertension). 3. Validate genes identified in Aims 1 and 2 using immunohistochemical analysis of renal tumor tissue microarrays containing the entire cohort of tumors.