ARSENIC BIOMARKER EPIDEMIOLOGY

我们建议对膀胱癌进行一项生物标志物病例对照研究 安徽省饮用水中砷污染状况调查 阿根廷科尔多瓦。初步研究显示膀胱增多 科尔多瓦两个县的癌症死亡率与总体相关风险 估计为2.5%。根据台湾的研究，增加的死亡率是 很可能是因为饮用水中的砷含量很高 (百至千杯/L)在两县多个地方。 拟议的研究项目将涉及150例膀胱癌和 将包括收集膀胱癌活检标本。肿瘤DNA将 使用三层方法分析基因改变， 用比较法筛选整个基因组的得失 基因组杂交(CGH)，对9号和17P号染色体的特异性分析 应用限制性片段长度多态性检测杂合性丢失 (RFLP)，并用聚合酶链式反应分析p53基因突变 反应-单链构象多态性分析(PCR-SSCP)。 将选择与病例位于同一两个县的控制 根据性别和日期与每宗个案匹配的选民登记名单 出生。将对病例和对照进行访谈，以获得终生 关于用水的住宅史和信息， 吸烟、饮食和其他变量。将获得砷的测量结果 针对每个病例和对照所使用的水源。剂量-反应分析 将对膀胱癌的关系进行调查 风险和接触砷。遗传基因的频率和模式 接触砷和未接触砷的膀胱肿瘤的变化将 被比较，以及评估潜在的协同作用 砷对吸烟的遗传毒性效应。此外, 将调查病例和对照之间的易感性差异。 通过识别谷胱甘肽S的存在或不存在- 口腔黏膜细胞转移酶GSTMI缺失型与尿液GSTMI缺失型比较 砷甲基化模式。这项研究的一个优点是，它将是 可能探索膀胱癌的遗传生物标记物并将其与 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年使用高砷的膀胱癌活检证实 智利北部的接触人群(400多杯/L)和较低的接触 美国人口(约百杯/L)。第二个优势是 提案研究表明，它有可能提供确凿的证据 关于砷摄取与癌症之间可能的因果关系 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.