MOLECULAR EPIDEMIOLOGY OF HUMAN CANCER

环境中的烟草烟雾和氡产生分子特征 非吸烟者的肺癌 越来越多的证据表明，环境致癌物可以离开 p53肿瘤抑制基因中遗传损伤的“指纹” 在人类肿瘤中。 这些数据表明，特定的致癌物质可能 与个体肿瘤有直接的联系。 被动吸烟与肺癌的发展有关， 流行病学研究和环境保护署 1992年12月，美国政府将二手烟列为A类致癌物。 该项目检查了非吸烟者的人类肺肿瘤组织， 遗传学证据将二手烟暴露与基因突变联系起来， p53抑癌基因。 具体假设包括：（一）频率 具有编码链偏好的G：C至T：A颠换将与 被动吸烟 (ii)易感因素包括 GSTM1和CYP1A1基因型将调节G：C到T：A的频率 颠换 氡导致肺癌中249met p53突变 与我们最初报道的肺组织中p53突变谱相反， 来自新墨西哥州铀矿工人的癌症和Bartsch等人的癌症， Taylor及其同事观察到一个突变热点249met，在肺组织中， 铀矿工的鳞状细胞癌而非腺癌 科罗拉多。 因此，我们启动了一项研究，直接测试 通过长期暴露正常人支气管， 上皮细胞的总剂量为4戈伊（相当于1460个工作剂量 水平月）的高线性能量转移α辐射，然后 使用基因型突变测定来确定p53突变 频率. 本研究的暴露阶段已完成。 我们 数据表明249met p53突变没有被诱导， p53突变谱与我们观察到的谱一致 在新墨西哥州的铀矿工人身上。

Environmental Tobacco Smoke and Radon Produce Molecular Signatures in Lung Cancers from Nonsmokers. Increasing evidence shows that environmental carcinogens can leave "fingerprints" of genetic damage in the p53 tumor suppressor gene within human tumors. These data suggest that specific carcinogens may be linked directly to individual tumors by telltale mutation profiles. Passive smoking has been linked to lung cancer development by several epidemiologic studies, and the Environmental Protection Agency classified secondhand smoke as a Class A carcinogen in December 1992. This project examines human lung tumor tissues from nonsmokers for genetic evidence linking secondhand smoke exposure to mutations in the p53 tumor suppressor gene. Specific hypotheses include: (i) Frequency of G:C to T:A transversions with a coding strand bias will correlate with passive smoke exposure. (ii) Susceptibility factors including GSTM1 and CYP1A1 genotypes will modulate the frequency of G:C to T:A transversions. Radon Produces 249met p53 Mutation in Lung Cancers from Uranium. In contrast to our initial report of the p53 mutation spectrum in lung cancer from uranium miners in New Mexico and that of Bartsch et al., Taylor and coworkers observed a mutation hotspot 249met, in lung squamous cell carcinoma but not adenocarcinoma from uranium miners in Colorado. Therefore, we have initiated a study to directly test the above hypothesis by chronically exposing normal human bronchial epithelial cells to a total of 4 Gy dose (equivalent to 1460 working level months) of high linear energy transfer alpha radiation and then using the genotypic mutation assay to determine the p53 mutation frequency. The exposure phase of this study has been completed. Our data indicate that 249met p53 mutations are not induced and that the p53 mutation spectrum is consistent with the spectrum observed by us in the uranium miners from New Mexico.