Bladder Cancer Risk and Genomic Alterations

膀胱癌风险和基因组改变

• 批准号: 7491001
• 负责人: Frederic M. Waldman
• 金额: $ 34.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-05 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491001
• 关键词: Bladder; Bladder Neoplasm; Cancer Etiology; Candidate Disease Gene; Case-Control Studies; Chromosome abnormality; Clinical; Collaborations; DNA amplification; Data; Diet; Division of Cancer Epidemiology and Genetics; Environment; Environmental Exposure; Environmental Risk Factor; Exposure to; Family history of; Gene Amplification; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genome; Genomic Instability; Genomics; Health; Histologic; Incidence; International; Invasive; Lamina Propria; Lead; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Multicenter Studies; Muscle; Mutation; Numbers; Outcome; PIK3CA gene; Paraffin; Pathway interactions; Patients; Recurrence; Research Design; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Spain; Staging; TP53 gene; Testing; Tobacco smoke; Trihalomethanes; Tumor Markers; Tumor Subtype; United States; base; cancer risk; cohort; comparative genomic hybridization; design; human PIK3CA protein; mortality; outcome forecast; prognostic; programs; size; tumor

DESCRIPTION (provided by applicant): This proposal is based on a model of urothelial cancer in which tumors develop along two histologic and molecular pathways: Low grade superficial tumors (pTaGi), which have frequent recurrences but rarely progress to muscle invasion; and high grade tumors which present either with early invasion into the lamina propria (pTiGs), or with more extensive muscle invasion (pT2-T4). We and others have identified a number of candidate genes and chromosomal alterations which are associated with these different pathways, and with clinical outcome. We hypothesize that overall genomic instability and specific genomic alterations are associated with environmental risk factors and with patient outcome. The overall design of this study is to characterize over 800 bladder tumors by array CGH and gene-specific analyses to define associations of molecular alterations with environmental exposures and with clinical outcome. These tumors have already been collected with associated data by our Spanish and NCI collaborators. We will validate associations between genomic alterations and patient outcome on a separate set of tumors collected as part of the International Bladder Tumor Marker Group. Specifically, we propose to: Aim i. Identify molecular alterations associated with environmental exposures in bladder cancers from the Spanish/NCI EPICURO Study. lA) Characterize molecular and genomic alterations in 250 pTa/Gi and 250 pT2-pT4/Gs tumors. Fraction genome altered and loci of specific alteration including DNA amplifications and homozygous deletions will be studied by array-CGH, expression signature by quantitative RT-PCR, and sequencing will identify mutations in pss and FGFRs. iB) Identify associations between environmental exposures and genomic/genetic alterations in the pTa/Gi and pT2-pT4 tumors applying a Case-Case- Control study design. Exposures to be tested will be tobacco smoke and trihalomethanes, which showed the strongest effects in the Case-Control study. Aim 2. Identify genomic and gene-specific alterations associated with patient outcome in both pTa and pT2-T4 tumor groups from the EPICURO study. Array-based CGH and gene-specific expression analyses will be tested to confirm genetic signatures predictive of patient outcome. Aims. A second cohort of 300 pTs muscle invasive tumors will be used to validate the predictive signatures tested in Aim 2. These tumors are being collected as part of International Bladder Tumor Marker Study to evaluate predictive markers in urothelial cancer. Relevance: Bladder cancer is a major cause of morbidity and mortality in the United States and internationally and is among the top 5 in cancer incidence. This study will identify whether environmental exposures lead to genetic alterations in tumors, and whether such alterations predict patient outcome.

描述（由申请人提供）：该提案基于尿路上皮癌模型，其中肿瘤沿着两种组织学和分子途径发展：低度浅表肿瘤（pTaGi），经常复发，但很少进展到肌肉侵袭；以及高级别肿瘤，其表现为早期侵入固有层（pTiGs），或更广泛的肌肉侵入（pT2-T4）。我们和其他人已经确定了许多与这些不同途径以及临床结果相关的候选基因和染色体改变。我们假设整体基因组不稳定性和特定基因组改变与环境风险因素和患者结果相关。本研究的总体设计是通过阵列 CGH 和基因特异性分析来表征 800 多种膀胱肿瘤，以确定分子改变与环境暴露和临床结果的关联。我们的西班牙和 NCI 合作者已经收集了这些肿瘤的相关数据。我们将在作为国际膀胱肿瘤标志物组一部分收集的一组单独的肿瘤上验证基因组改变与患者结果之间的关联。具体来说，我们建议： 目标 i。从西班牙/NCI EPICURO 研究中确定与膀胱癌环境暴露相关的分子改变。 1A)表征250 pTa/Gi和250 pT2-pT4/Gs肿瘤中的分子和基因组改变。将通过阵列-CGH 研究基因组改变的部分和特定改变的位点，包括 DNA 扩增和纯合缺失，通过定量 RT-PCR 进行表达特征研究，并且测序将识别 pss 和 FGFR 中的突变。 iB) 应用病例对照研究设计，确定 pTa/Gi 和 pT2-pT4 肿瘤中环境暴露与基因组/遗传改变之间的关联。要测试的暴露将是烟草烟雾和三卤甲烷，这在病例对照研究中显示出最强的影响。目标 2. 在 EPICURO 研究中确定与 pTa 和 pT2-T4 肿瘤组患者结果相关的基因组和基因特异性改变。将测试基于阵列的 CGH 和基因特异性表达分析，以确认预测患者结果的遗传特征。目标。第二组 300 个 pT 肌肉浸润性肿瘤将用于验证目标 2 中测试的预测特征。这些肿瘤作为国际膀胱肿瘤标志物研究的一部分被收集，以评估尿路上皮癌的预测标志物。相关性：膀胱癌是美国和国际上发病和死亡的主要原因，并且位居癌症发病率前 5 位。这项研究将确定环境暴露是否会导致肿瘤的基因改变，以及这种改变是否可以预测患者的预后。