ARSENIC BIOMARKER EPIDEMIOLOGY

我们建议进行膀胱癌生物标志物病例对照研究， 调查该省饮用水中砷的影响 阿根廷科尔多瓦 初步研究显示膀胱增大 科尔多瓦两个县的癌症死亡率， 估计为2.5。 根据台湾的研究，死亡率的增加是 很可能是因为饮用水中含有高含量的砷 （在100和1000 mug/L之间）在两个县的一些地方。 该研究计划将涉及150例膀胱癌， 将包括收集膀胱肿瘤活检标本。 肿瘤DNA将 使用三层方法分析遗传改变， 使用比较基因组筛选整个基因组的得失， 基因组杂交（CGH），染色体9和17 p的特异性分析， 限制性片段长度多态性杂合性丢失 （RFLP），并使用聚合酶链分析p53基因的突变 反应-单链构象多态性分析（PCR-SSCP）。 将选择居住在与病例相同的两个县的对照 按性别和日期分列的与每个案件相匹配的选民登记名单 出生 将对病例和对照进行访谈，以获得生存期 住宅历史和有关用水的信息， 吸烟、饮食和其他变量。 将获得砷测量结果 每个病例和对照使用的水源。 剂量反应分析 将调查膀胱癌与 砷的风险和暴露。 基因突变的频率和模式 砷暴露和未暴露病例膀胱肿瘤的改变将 沿着评估潜在的协同作用， 砷对吸烟的遗传毒性作用。 此外，本发明还提供了一种方法， 将研究病例和对照之间的易感性差异 通过鉴定谷胱甘肽S- 转移酶GSTMI无效基因型在颊细胞和比较尿 砷甲基化模式。 这项研究的一个优点是， 可能探索膀胱肿瘤的遗传生物标志物，并将其与 与砷和吸烟有关的风险状况。 这些发现将是 在第4年和第5年使用高砷的膀胱肿瘤活检证实， 智利北方的暴露人群（超过400 mug/L）和较低的暴露水平 美国人口（约100 mug/L）。 第二种力量 建议的研究是，它有可能提供明确的证据， 关于砷摄入与 膀胱癌，并建立剂量反应关系，用于 风险评估

We propose to conduct a biomarker case-control study of bladder cancer to investigate the effects of arsenic in drinking water in the province of Cordoba, Argentina. Preliminary studies have shown increased bladder cancer mortality in two counties in Cordoba with an overall relateive risk estimate of 2.5. Based on studies in Taiwan, this increased mortality is most likely due to drinking water containing high levels of arsenic (between 100 and 1000 mug/L) in a number of localities in the two counties. Thr proposed research project will involve 150 cases of bladder cancer and will include collection of bladder tumor biopsy specimens. Tumor DNA will be analyzed for genetic alterations using a three-tiered approach, with screening of the entire genome for gains and loses using comparative genomic hybridization (CGH), specific analyses of chromosomes 9 and 17p for loss of heterozygosity using restriction fragment length polymorphism (RFLP), and analysis of the p53 gene for mutations using polymerase chain reaction-single-strand conformation polymorphism analysis (PCR-SSCP). Controls residing in the same two counties as the cases will be selected from voter registration lists matched to each case by sex and date of birth. Cases and controls will be interviewed to obtain lifetime residential histories and information concerning consumption of water, smoking, diet, and other variables. Arsenic measurements will be obtained for water sources used by each case and control. Dose-response analyses will be conducted investigating the relationship between bladder cancer risk and exposure to arsenic. The frequency and pattern of genetic alterations in bladder tumors of arsenic exposed and unexposed cases will be compared, along with assessment of the potential synergistic action of arsenic on genotoxic effects of cigarette smoking. In addition, susceptibility differences between cases and controls will be investigated by identifying the presence or presence or absence of the glutathione S- transferases GSTMI null genotypes in buccal cells and by comparing urinary arsenic methylation patterns. One strength of the study is that it will be possible to explore genetic biomarkers in bladder tumors and link these to risk status related to arsenic and smoking. These findings will be confirmed in years 4 and 5 using bladder tumor biopsies from a high arsenic exposure population in northern Chile (over 400 mug/L) and a lower exposure population in the U.S. (around 100 mug/L). A second strength of the proposal study is that it has potential to provide the definitive evidence concerning the probable causal association between arsenic ingestion and bladder cancer, and to establish the dose-response relationship for use in risk assessment.