GENETIC & ENVIRONMENTAL RISK FACTORS FOR BLADDER CANCER

描述（由申请人提供）：工业染料制造中使用的芳胺的职业暴露是人类膀胱癌的第一个已知原因。这些致癌性芳胺，特别是4-氨基联苯（4-ABP）、-萘胺和联苯胺，也含有在烟草烟雾中，是最有可能导致吸烟者膀胱癌发病率升高的病原体。芳胺的氧化被认为是将这些化学物质转化为能够对尿路上皮细胞造成DNA损伤的致癌代谢物的关键第一步。染发剂是人类体内芳胺的另一个重要来源，我们最近发现，女性持续使用永久性染发剂是患膀胱癌的一个危险因素，尤其是那些缺乏芳胺解毒酶的人。随后，在美国一家商店购买的商业染发剂中检测到4-ABP。然后，使用4-ABP的血红蛋白加合物作为暴露的生物标志物，我们发现其他可能是弥漫性的4-ABP暴露源可能与非吸烟者的膀胱癌有关。因此，最新的证据表明，芳胺暴露是美国膀胱癌的主要原因。十年前，我们报道了尽管吸烟习惯相似，但美国白人患膀胱癌的风险比中国男性高3倍的原因，可能是在遗传控制下缺乏芳胺解毒酶的前人群中患病率更高。我们利用这一发现，开展了一项基于人群的病例对照研究，其中包括洛杉矶和中国上海的组成部分，以探索在芳胺暴露个体中决定膀胱癌风险的主要遗传因素。这个已经完成的数据库包括大约1300例膀胱癌病例（洛杉矶750例，上海550例）和大约相同数量的对照受试者。我们最初的目标是研究选择的多态性、芳胺代谢基因型/表型在膀胱癌中的作用，以及在洛杉矶成分中，使用血红蛋白加合物作为芳胺暴露的生物标志物来检查非吸烟相关膀胱癌。在此应用中，我们的目标是通过对洛杉矶/上海数据库的以下扩展，更全面地了解芳胺与膀胱癌的病因学联系：(1)完成上海受试者的芳胺血红蛋白加合物测量，以比较这些加合物对洛杉矶和上海受试者风险的各自影响；(2)加入参与芳胺代谢、细胞氧化应激反应和DNA修复的基因型；(3)开发贝叶斯分层统计模型，以便对膀胱癌中多基因-芳胺相互作用进行有效的、途径驱动的检查。本研究的最终目的是评估个体膀胱癌的风险，以进行预防干预。

DESCRIPTION (provided by applicant): Occupational exposure to arylamines used in the manufacturing of industrial dyes was the first known cause of human bladder cancer. These carcinogenic arylamines, specifically, 4-aminobiphenyl (4-ABP), beta-naphthylamine, and benzidine, are also contained in tobacco smoke, and are the most likely causative agents responsible for the raised rates of bladder cancer in smokers. Oxidation of arylamines is recognized as a critical first step in turning these chemical species into their carcinogenic metabolites capable of causing DNA damage to urothelial cells. Hair dyes represent another substantial source of arylamines in humans, and we recently showed that sustained use of permanent hair dyes in women is a risk factor for bladder cancer, especially among those deficient in arylamine detoxifying enzymes. Subsequently, 4-ABP was detected in bottles of commercial hair dyes bought in a US store. Then, using hemoglobin adducts of 4-ABP as a biomarker of exposure, we showed that other, presumably diffuse, sources of 4-ABP exposure may be related to bladder cancer in nonsmokers. Thus, the latest evidence indicates arylamine exposure as the primary cause of bladder cancer in the United States. Ten years ago, we reported that a reason for the 3-fold increased risk of bladder cancer in US white versus Chinese men despite their comparable smoking habits may be the higher prevalence in the former population of individuals with deficient arylamine-detoxifying enzymes, which are under genetic control. We capitalized on this finding and launched a population-based case-control study involving both a Los Angeles and a Shanghai, China component to explore genetic factors that play a major role in determining bladder cancer risk in arylamine-exposed individuals. This already completed database consists of roughly 1300 cases of incident bladder cancer (750 cases in Los Angeles, 550 cases in Shanghai) and about an equal number of control subjects. Our initial goals were to investigate the roles of selected polymorphic, arylarnine-metabolizing genotypes/phenotypes in bladder cancer, and in the Los Angeles component, to use hemoglobin adducts as biomarkers of exposure to arylamines in examining nonsmoking-related bladder cancer. In this application, we aim for a more comprehensive understanding of the arylamine-bladder cancer etiologic link through the following extensions on our Los Angeles/Shanghai database: (1) Completion of arylamine hemoglobin adduct measurements on Shanghai subjects in order to compare the respective effects of these adducts on risk between Los Angles and Shanghai study subjects; (2) Addition of genotypes involved in arylamine metabolism, in cellular response to oxidative stress and in DNA repair; and (3) Development of a Bayesian hierarchical statistical model to allow for an efficient, pathway-driven examination of multiple gene-arylamine interactions in bladder cancer. The ultimate goal of this research is to assess individual bladder cancer risk for the purpose of preventive interventions.