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）发病率相关。然而，这些危险因素导致RCC的机制，可能是通过改变特定基因起作用，是未知的。我们假设在肾癌中检测到的特定基因组改变（DNA获得或丢失）与肾癌风险因素相关。我们建议分析风险因素和肾肿瘤基因组改变之间的关联，这些风险因素和基因组改变是由美国国家癌症研究所和国际癌症研究协会（IARC）进行的东欧肾细胞癌研究（EERCC）的一部分。我们假设肾癌中特定的基因组改变（DNA获得或丢失）与肾癌危险因素和肿瘤进展相关。我们的目标是： 本研究的总体设计是通过阵列CGH表征700多个肾肿瘤，以定义基因组改变及其与临床变量、暴露和遗传风险因素的相关性。 1.确定与常规（透明细胞）肾癌肿瘤分期相关的基因组改变。基于阵列的CGH将用于定义根据分期（I-IV）分组的200个传统RCC的DNA中的拷贝数增加和损失，包括DNA扩增和纯合缺失。 2.使用IARC肾癌患者病例对照队列，确定基因组改变与统计学显著性暴露、职业和遗传风险因素的相关性。除目标1中研究的肿瘤外，还将通过阵列CGH对另外500个肿瘤进行表征。将根据暴露史选择患者，以产生最大的分析把握度（富集最高暴露组）。需要考虑的风险因素包括吸烟、职业和环境暴露（三氯乙烯、多环芳烃、石油产品、石棉和重金属）以及改变肾功能的因素（肥胖和高血压）。 3.使用包含整个肿瘤队列的肾肿瘤组织微阵列的免疫组织化学分析，在目的1和2中鉴定出的p53基因。

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.