Renal cancer genomic alterations-environmental risk(RMI)

肾癌基因组改变-环境风险（RMI）

• 批准号: 6953208
• 负责人: Frederic M. Waldman
• 金额: $ 29.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953208
• 关键词: asbestos; cancer risk; comparative genomic hybridization; environmental exposure; gene environment interaction; genetic polymorphism; genetic susceptibility; high performance liquid chromatography; human tissue; immunocytochemistry; kidney function; microarray technology; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplastic process; renal cell carcinoma; smoking; trichloroethylene

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.

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，这些危险因素导致肾细胞癌的机制尚不清楚，可能是通过改变特定基因而发挥作用。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）与肾癌危险因素相关。我们建议分析危险因素与肾肿瘤基因组改变之间的关联，这些肾肿瘤是东欧肾细胞癌研究（EERCC）的一部分，该研究由国家癌症研究所和国际癌症研究协会（IARC）进行。我们假设肾癌的特定基因组改变（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 来表征 700 多种肾肿瘤，以确定基因组改变及其与临床变量、暴露和遗传风险因素的关联。 1. 识别与传统（透明细胞）肾癌肿瘤分期相关的基因组改变。基于阵列的 CGH 将用于定义来自根据阶段 (I-IV) 分组的 200 个常规 RCC 的 DNA 中的拷贝数增加和损失，包括 DNA 扩增和纯合缺失。 2. 确定基因组改变与使用 IARC 肾癌患者病例对照队列定义的统计显着暴露、职业和遗传风险因素之间的关联。除了目标 1 中研究的那些之外，还将通过阵列 CGH 来表征另外 500 个肿瘤。将根据患者的暴露史选择患者，以产生最大的分析能力（丰富最高暴露组）。要考虑的危险因素包括吸烟、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. 使用包含整个肿瘤组的肾肿瘤组织微阵列的免疫组织化学分析来验证目标 1 和 2 中鉴定的基因。