Renal cancer genomic alterations and environmental risk(RMI)

描述（由申请人提供）：许多环境、职业和生活方式因素与肾细胞癌（RCC）的发病率有关。然而，这些风险因素导致RCC的机制，可能是通过改变特定的基因，是未知的。我们假设在肾癌中检测到的特定基因组改变（DNA的增加或减少）与肾癌的危险因素有关。我们建议分析作为国家癌症研究所和国际癌症研究协会（IARC）开展的东欧肾细胞癌研究（EERCC）的一部分收集的肾肿瘤危险因素与基因组改变之间的关系。我们假设肾癌中特定的基因组改变（DNA的增加或减少）与肾癌的危险因素和肿瘤的进展有关。我们的目标是：

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.