GENETIC & ENVIRONMENTAL RISK FACTORS FOR BLADDER CANCER

描述（由申请人提供）：职业暴露于工业染料生产中使用的芳胺是人类膀胱癌的第一个已知原因。这些致癌的芳香胺，特别是4-氨基联苯（4-ABP），β-萘胺和联苯胺，也包含在烟草烟雾中，并且是导致吸烟者膀胱癌发病率升高的最可能的致病因子。芳胺的氧化被认为是将这些化学物质转化为致癌代谢物的关键第一步，这些代谢物能够引起尿路上皮细胞的DNA损伤。染发剂是人类芳香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膀胱癌的一个危险因素，特别是那些缺乏芳香胺解毒酶的人。随后，在美国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。10年前，我们报道了美国白色男性与中国男性相比，尽管他们的吸烟习惯相似，但膀胱癌风险增加3倍的原因可能是在前人群中缺乏芳香胺解毒酶的个体患病率较高，这是受遗传控制的。我们利用这一发现，并启动了一项以人群为基础的病例对照研究，包括洛杉矶和上海，中国的组成部分，以探讨遗传因素，在确定膀胱癌的风险在芳胺暴露的个人发挥了重要作用。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组。我们最初的目标是研究选择的多态性，芳基胺代谢基因型/表型在膀胱癌中的作用，并在洛杉矶的组成部分，使用血红蛋白加合物作为生物标志物暴露于芳基胺在检查非吸烟相关的膀胱癌。在本申请中，我们的目标是通过对我们的洛杉矶/上海数据库的以下扩展来更全面地了解芳胺-膀胱癌病因学联系：（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研究受试者之间风险的各自影响;（2）增加参与芳香胺代谢、细胞对氧化应激的反应和DNA修复的基因型;和（3）开发贝叶斯分层统计模型，以允许对膀胱癌中多个基因-芳香胺相互作用进行有效的、途径驱动的检查。本研究的最终目标是评估个体膀胱癌风险，以进行预防性干预。

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.