Bladder Cancer Risk and Genomic Alterations

描述(申请人提供)：这项建议是基于尿路上皮癌的模型，其中肿瘤沿着两条组织学和分子通路发展：低级别浅表肿瘤(PTaGi)，它经常复发，但很少进展为肌肉侵犯；高级别肿瘤，表现为早期侵犯固有层(PTiGs)，或有更广泛的肌肉侵犯(pt2-t4)。我们和其他人已经确定了一些候选基因和染色体变化，这些基因和染色体变化与这些不同的途径和临床结果有关。我们假设，总体基因组不稳定和特定的基因组改变与环境风险因素和患者预后相关。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800多个膀胱肿瘤，以确定分子变化与环境暴露和临床结果的关系。这些肿瘤已经由我们的西班牙和NCI合作者收集了相关数据。我们将在作为国际膀胱癌标记物小组一部分收集的一组单独的肿瘤上验证基因组改变和患者预后之间的相关性。具体地说，我们建议：目的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。A)研究250例PTA/GI和250例PT2-PT4/Gs肿瘤的分子和基因组改变。部分基因组改变和包括DNA扩增和纯合子缺失在内的特异性改变的基因座将通过阵列-CGH进行研究，表达特征将通过定量RT-PCR进行研究，测序将识别PSS和FGFRs的突变。Ib)应用病例-病例-对照研究设计，确定环境暴露与PTA/GI和pt2-PT4肿瘤的基因组/基因改变之间的关系。被测试的暴露将是烟草烟雾和三卤代甲烷，这两种物质在病例对照研究中显示出最强的影响。目的2.从EPICURO研究中确定PTA和PT2-T4肿瘤组中与患者预后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签名。目标。第二组300例肌肉浸润性肿瘤将用于验证在AIM 2中测试的预测标志。这些肿瘤是作为国际膀胱肿瘤标志物研究的一部分收集的，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率和死亡率的主要原因，是癌症发病率的前五名之一。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。

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.