The Molecular Epidemiology of Bladder Cancer

描述（由申请人提供）：膀胱癌是最常见的泌尿系统恶性肿瘤，每年在美国造成相当数量的死亡。除了吸烟和某些职业暴露外，这种恶性肿瘤的病因在很大程度上仍无法解释。越来越多的证据表明，膀胱癌是由具有不同分子病理特征的异质性肿瘤组成的。此外，体细胞变化的模式（包括肿瘤抑制基因的启动子甲基化沉默和TP53改变）可能反映了特定致癌物的暴露，并作为侵袭性（即致命性）疾病的标志物。因此，我们建议研究暴露于已知和可疑的膀胱癌致癌物在以下方面的病因学作用：(1)目前已知的导致膀胱癌发生的肿瘤抑制基因的启动子甲基化沉默；(2)全局低甲基化（即LINE元件的低甲基化）。此外，我们将确定甲基化改变对临床表型（如肿瘤分期和分级）和膀胱癌患者生存的影响。最后，采用新颖的统计方法，我们将建立一个体细胞表观遗传和TP53改变的模型，以研究暴露史（如吸烟、职业、饮食、砷暴露和染发剂使用）和DNA修复和致癌物代谢基因的变化是否改变膀胱癌分子病理表型和临床结果的相关性。我们的研究利用了新罕布什尔州以人群为基础的膀胱癌调查，其中包括大约850名膀胱癌患者，他们的详细暴露、医疗和家族史、血液或口腔DNA以及诊断性肿瘤组织样本都已成功确定。此外，我们正在利用新的统计方法来确定与膀胱癌相关的沉默基因的病因学和临床重要性。我们的研究结果将有助于阐明环境和遗传因素在膀胱癌发病中的作用，这些因素诱发膀胱癌的潜在机制，以及分子标记在预测膀胱癌预后中的应用。因此，这项工作将使用一种新的方法来评估导致膀胱癌的沉默基因的重要性。它将发展新的方法，扩大我们对暴露如何诱发膀胱癌的理解，展示分子标记在预测预后方面的效用，并阐明多种暴露在膀胱癌中的因果作用。

DESCRIPTION (provided by applicant): Bladder cancer is the most common urologic malignancy and is responsible for an appreciable number of deaths each year in the USA. Aside from tobacco smoking and certain occupational exposures, the etiology of this malignancy remains largely unexplained. Accumulating evidence indicates that bladder cancer comprises a heterogeneous group of tumors with distinct molecular-pathologic characteristics. Moreover, the pattern of somatic changes (including promoter methylation silencing of tumor suppressor genes and TP53 alterations) may reflect exposures to specific carcinogens and serve as markers of aggressive, i.e., fatal, disease. Therefore, we propose to investigate the etiologic role of exposure to known and suspected bladder carcinogens on (1) promoter methylation silencing of the tumor suppressor genes currently known to contribute to the genesis of bladder cancer and (2) global hypomethylation (i.e., hypomethylation of LINE elements). Further, we will determine the impact of methylation alterations on clinical phenotype (e.g., tumor stage and grade) and bladder cancer patient survival. Lastly, applying novel statistical methods, we will build a model of somatic epigenetic and TP53 alterations to examine whether exposure history (e.g., cigarette smoking, occupation, diet, arsenic exposure, and hair dye use) and variation in DNA repair and carcinogen metabolism genes modify the associations with molecular-pathologic phenotype and clinical outcome in bladder cancer. Our study takes advantage of population-based investigations of bladder cancer in New Hampshire encompassing approximately 850 bladder cancer patients on whom detailed exposure, medical and family history, blood or buccal DNA, and diagnostic tumor tissue samples are being successfully ascertained. In addition, we are utilizing novel statistical approaches to determine the etiologic and clinical importance of silencing genes involved in bladder cancers. The results of our study will help clarify the role of environmental and genetic factors in the pathogenesis of bladder cancer, the underlying mechanisms of bladder cancer induction by these factors, and the utility of molecular markers in predicting bladder cancer prognosis. This work, then, will use a novel approach to evaluate the importance of silencing genes that cause bladder cancer. It will develop approaches that will enlarge our understanding of how exposures induce bladder cancer, demonstrate the utility of molecular markers in predicting prognosis and clarify the causal role of many exposures in bladder cancer.