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，这些危险因素导致肾癌的机制尚不清楚，可能是通过特定基因的改变而起作用。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)与肾癌危险因素有关。我们建议分析由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)中收集的肾脏肿瘤中的危险因素和基因组变化之间的关系。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有关。我们的目标是： 这项研究的总体设计是通过阵列CGH来确定700多个肾脏肿瘤的特征，以确定基因组变化及其与临床变量、暴露和遗传风险因素的关联。 1.确定与传统(透明细胞)肾癌的肿瘤分期相关的基因组改变。基于阵列的CGH将用于定义200例常规肾细胞癌DNA的拷贝数增减，包括DNA扩增和纯合子缺失，按阶段(I-IV)分组。 2.使用IARC病例对照队列确定肾癌患者的基因组改变与统计学上显著的暴露、职业和遗传风险因素之间的关系。除了AIM 1中研究的那些肿瘤外，还将有500个肿瘤通过阵列CGH进行表征。患者将根据他们的暴露历史进行选择，以产生最大的分析能力(对最高暴露组进行丰富)。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来验证AIMS 1和AIMS 2中识别的基因。

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.