BPDE Sensitivity at 9p21 and Bladder Cancer Risk

描述(由申请人提供)： 这项拟议的研究将建立在正在进行的一项名为“膀胱癌的遗传易感性：分子流行病学方法”(R01 CA74880，申请人：吴喜峰)的膀胱癌研究中的广泛流行病学数据库和标本库的基础上。这项家长资助包括一个多学科的研究小组，他们在病例对照研究中使用分子流行病学方法，共同的目标是确定烟草引起的膀胱癌易感性的个体间差异。最近的证据表明，烟草烟雾的成分苯并[(])芘(B[(]P))的代谢产物苯并[(])芘二醇环氧化物(BPDE)的敏感性是一种体质现象，是几种与烟草相关的癌症的危险因素，如肺癌、头颈癌和膀胱癌。有必要进一步阐明BPDE的分子靶点。染色体9p物质丢失是膀胱癌最常见的基因组改变之一。此外，9p21和p16的改变在慢性吸烟者的上皮细胞中也是常见的。拟议研究的具体目标是：1)。[目的]探讨200例膀胱癌患者外周血淋巴细胞(PBL)中BPDE诱发的染色体9p21点突变是否比200例与之性别、年龄(5岁)和种族相匹配的对照组更为常见。我们的工作假设是，9p21BPDE敏感性可能反映了特定基因座对烟草吸烟致癌物的遗传易感性，染色体9p21可能是烟草烟雾中致癌物的分子靶标，具有这种异常的个体患膀胱癌的风险增加。2)。目的：检测50例膀胱癌患者尿液细胞9p21自发畸变率及淋巴细胞9p21畸变率与相应尿液标本的相关性。我们的工作假设是，外周血淋巴细胞的像差准确地反映了靶组织的变化。3)。通过将流行病学数据与分子细胞遗传学数据相结合，评估遗传标记与年龄、性别、吸烟状况和营养状况之间的关系。这些数据是在父母的资助中例行收集的。建议的敏感性标记物可能会作为生物标记物来识别高危人群，然后这些高危人群可以成为密集戒烟计划的目标，并可以参加化学预防试验。

DESCRIPTION (provided by applicant): This proposed study will build upon the extensive epidemiologic database and specimen repository derived from an ongoing bladder cancer study entitled "Genetic Susceptibility to Bladder Cancer: A Molecular Epidemiologic Approach" (R01 CA74880, applicant: Xifeng Wu). This parent grant includes a multidisciplinary group of researchers using a molecular epidemiologic approach in a case-control study with the common goal of identifying inter-individual differences in susceptibility to tobacco-induced bladder carcinogenesis. Recent evidence has suggested that sensitivity to benzo[(]pyrene diol epoxide (BPDE), the metabolic product of benzo[(]pyrene (B[(]P), a constituent of tobacco smoke, is a constitutional phenomenon and is a risk factor for several tobacco-related cancers such as lung, head and neck, and bladder cancers. There is a need for further elucidation of the molecular targets of BPDE. Loss of chromosome 9p material is one of the most frequent genomic alterations in bladder cancer. In addition, alterations of 9p21 and p16 are frequently seen in the epithelial cells of chronic smokers. The specific aims of the proposed study are: 1). To determine whether BPDE-induced chromosome aberrations on 9p21 are more common in the cultured peripheral blood lymphocyte (PBLs) of 200 bladder cancer patients than those of 200 controls matched to the cases on sex, age ( 5 years) and ethnicity. Our working hypothesis is that 9p21 BPDE sensitivity may reflect inherited genetic susceptibility of a specific locus to carcinogens in tobacco smoking, that chromosome 9p21 may be the molecular target of carcinogens contained in tobacco smoke, and that individuals with such aberrations are at an increased risk for bladder cancer. 2). To determine frequency of spontaneous 9p21 aberrations occur in cells in urine from 50 cases of bladder cancer patients and whether there is a correlation between level of 9p21 aberrations in lymphocytes and corresponding urine samples. Our working hypothesis is that aberrations in PBLs accurately reflect changes in the target tissue. 3). To assess the associations between the genetic marker and age, sex, cigarette smoking status, and nutrition status by integrating epidemiologic data with the molecular cytogenetic data. These data are being routinely collected in the parent grant. The proposed susceptibility marker may be useful as biomarkers to identify high-risk populations that could then be targeted for intensive smoking-cessation programs and could be enrolled into chemoprevention trials.