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）：该建议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：低级浅表肿瘤（PTAGI），这些肿瘤（PTAGI）经常复发，但很少会发展为肌肉入侵；和高级肿瘤，它们会早期入侵椎板（PTIG）或更广泛的肌肉入侵（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。我们假设总体基因组不稳定性和特定的基因组改变与环境风险因素以及患者结局有关。这项研究的总体设计是通过阵列CGH和基因特异性分析来表征超过800个膀胱肿瘤，以定义分子改变与环境暴露和临床结果的关联。这些肿瘤已经由我们的西班牙和NCI合作者收集了相关的数据。我们将验证基因组改变与患者结局之间的关联，这是一组作为国际膀胱肿瘤标记组的一部分收集的肿瘤。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中环境暴露有关的分子改变。 LA）表征250 pta/gi和250个PT2-PT4/GS肿瘤中的分子和基因组改变。特定改变的分数基因组改变和基因座，包括DNA扩增和纯合缺失，通过Array-CGH，通过定量RT-PCR进行表达签名，测序将识别PSS和FGFR中的突变。 IB）确定PTA/GI和PT2-PT4肿瘤的环境暴露与基因组/遗传改变之间的关联，该肿瘤应用了病例控制研究设计。要测试的暴露将是烟草烟雾和三甲米甲烷，这在病例对照研究中显示出最强的影响。 AIM 2。从Epicuro研究中确定与患者结局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，以确认可预测患者预后的遗传特征。目标。将使用第二个300分的肌肉侵入性肿瘤来验证AIM 2中测试的预测特征。这些肿瘤是作为国际膀胱肿瘤标记研究的一部分收集的，以评估尿尿皮细胞癌的预测标记。相关性：在美国和国际上，膀胱癌是发病率和死亡率的主要原因，并且是癌症发病率前5名。这项研究将确定环境暴露是否会导致肿瘤的遗传改变，以及这种改变是否可以预测患者的结果。