The Molecular Epidemiology of Bladder Cancer

膀胱癌的分子流行病学

• 批准号: 7541681
• 负责人: Karl Timothy Kelsey
• 金额: $ 42.89万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541681
• 关键词: Arsenic; Biological Markers; Bladder; Bladder Neoplasm; Blood; Cancer Patient; Cancer Prognosis; Carcinogen Metabolism; Carcinogen exposure; Carcinogens; Case-Control Studies; Cessation of life; Characteristics; Clinical; Code; DNA; DNA Repair; Data; Diagnostic; Diagnostic Neoplasm Staging; Diet; Disease; Disease Pathway; Elements; Employee Strikes; Epidemiologic Studies; Epigenetic Process; Etiology; Exposure to; Family history of; Gene Mutation; Gene Silencing; Gene-Modified; Genes; Genetic; Genetic Polymorphism; Genomics; Hair Dyes; Heterogeneity; Hypermethylation; Indium; Investigation; Knowledge; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Metabolism; Methylation; Modeling; Molecular; Molecular Epidemiology; New Hampshire; Numbers; Occupational Exposure; Occupations; Outcome; Parents; Participant; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Population; Recording of previous events; Role; Smoke; Smoking; Statistical Methods; TP53 gene; Techniques; Testing; Tissue Sample; Tobacco smoking; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; Tumor stage; Variant; Work; Xenobiotics; base; bladder Carcinoma; carcinogenesis; cigarette smoking; clinical phenotype; genetic association; novel; novel strategies; outcome forecast; prognostic; promoter; repaired; tumor; urologic

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.

描述(申请人提供)：膀胱癌是最常见的泌尿系恶性肿瘤，每年在美国造成可观的死亡人数。除了吸烟和某些职业接触外，这种恶性肿瘤的病因在很大程度上仍然无法解释。越来越多的证据表明，膀胱癌是一组具有不同分子病理特征的异质性肿瘤。此外，体细胞变化的模式(包括肿瘤抑制基因启动子甲基化沉默和TP53改变)可能反映了对特定致癌物的暴露，并作为侵袭性疾病的标志，即致命的疾病。因此，我们建议调查暴露在已知和可疑的膀胱癌致癌物中的病因学作用：(1)目前已知有助于膀胱癌发生的抑癌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(例如，肿瘤分期和分级)和膀胱癌患者生存的影响。最后，应用新的统计学方法，我们将建立一个体细胞表观遗传学和TP53改变的模型，以检验暴露史(例如吸烟、职业、饮食、砷暴露和染发剂使用)以及DNA修复和致癌物代谢基因的变化是否会改变膀胱癌的分子病理表型和临床结果的相关性。我们的研究利用了新汉普郡对膀胱癌的人口调查，涵盖了大约850名膀胱癌患者，他们的详细暴露、病史和家族史、血液或颊DNA以及诊断肿瘤组织样本正在成功确定。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，以及分子标志物在预测膀胱癌预后方面的应用。因此，这项工作将使用一种新的方法来评估沉默导致膀胱癌的基因的重要性。它将开发一些方法，扩大我们对暴露如何诱发膀胱癌的理解，展示分子标志物在预测预后方面的效用，并澄清许多暴露在膀胱癌中的因果作用。