Genetic And Environmental Factors In Lung Cancer

目的：这项研究的目的是检查影响肺癌风险的遗传因素，并考虑与环境因素的交互作用。为此，我继续在两项研究中考察遗传易感性在肺癌病因中的作用。第一项是对洛杉矶县的非裔美国人和高加索人进行的病例对照研究。S·伦敦在南加州大学任教期间完成了受试者登记(356例病例和731名对照受试者)。在过去的一年里，我们研究了几个DNA修复基因-XPD、XRCC1和XRCC3的多态。我还参与了一个国际合作项目，该项目汇集了基因多态和肺癌风险研究的原始数据，以提高检查基因与环境相互作用的能力。另一项研究是由NCI资助的18244名上海男性的队列研究。这是为数不多的前瞻性采集血液和尿液样本以及足够比例的吸烟者以产生足够的肺癌病例的队列研究之一。我们一直在对259例肺癌和匹配对照进行嵌套病例对照研究。DNA的来源是血清，这带来了挑战，因为与全血相比，遗传物质的数量较少。在过去的一年里，我们研究了异硫氰酸酯饮食摄入量的尿液生物标志物与谷胱甘肽S转移酶基因多态性之间的关系，这些基因参与了异硫氰酸酯的排泄。上海的队列提供了一个独特的机会来研究这种基因-饮食相互作用，因为异硫氰酸酯的蔬菜来源摄入量很高。预期收集的尿样能够评估异硫氰酸酯，而不受疾病过程的影响。我们还研究了肺癌风险与CYP1A1基因多态之间的关系。我们目前正在分析与诊断前血清胰岛素样生长因子-1及其主要结合蛋白IGFBP-3水平有关的肺癌风险数据。这些样本在NIEHS与Greg Travlos博士合作进行了广泛的实验室分析方法比较后进行了分析。由于水平可能会因疾病过程或治疗而改变，因此需要前瞻性分析的结果来评估这种联系。程序和技术：洛杉矶的病例对照研究使用标准病例对照方法。人口控制是从驾照和医疗保险名单中登记的。上海的研究分析使用了前瞻性队列中发生肺癌的嵌套病例对照研究。基因分型是通过基于聚合酶链式反应的方法进行的。成就：到目前为止，关于非裔美国人和18岁高加索人的基因多态和肺癌风险的研究已经发表了一些出版物。在过去的一年里，我们已经有两篇关于DNA修复多态和肺癌风险的手稿被接受。在上海的队列研究中，我们发表了异硫氰酸酯摄入量与GSTM1和GSTT1基因多态之间存在基因-饮食相互作用的证据，这些基因多态参与了异硫氰酸酯的代谢。我们在这个队列中对IGF-1和IGF1-BP3的分析代表了对这种联系的第一次前瞻性研究。

Aims: The aim of this research is to examine genetic factors that influence the risk of lung cancer and to consider interactions with environmental factors. To this end, I continue to examine the role of genetic susceptibility in the etiology of lung cancer in two studies. The first is a case-control study of African-Americans and Caucasians in Los Angeles County. Subject enrollment (356 cases and 731 control subjects) was completed by S. London while she was a faculty member at the University of Southern California. During the past year, we have examined polymorphisms in several DNA repair genes - XPD, XRCC1 and XRCC3. I am also participating in an international collaborative project to pool original data from studies of genetic polymorphisms and lung cancer risk to improve power to examine gene-environment interactions. The other study is an NCI-funded cohort of 18,244 Shanghai men. This is one of the few cohort studies with prospectively collected blood and urine samples and an adequate proportion of smokers to yield sufficient lung cancer cases. We have been conducting nested case-control studies of 259 incident lung cancers and matched controls. The DNA source is from serum which presents challenges because of the smaller quantity of the genetic material compared to whole blood. In the past year we have examined the relation between a urinary biomarker of dietary intake of isothiocyanates and polymorphisms in glutathione S-transferase genes that are involved in their excretion. The Shanghai cohort offers a unique opportunity to examine this gene-diet interaction because of the high intake of vegetable sources of isothiocyanates. The prospectively collected urine samples enable assessment of isothiocyanates unbiased by effects of the disease process. We have also examined the relation between lung cancer risk and CYP1A1 polymorphisms. We are currently analyzing data on lung cancer risk in relation to prediagnostic serum levels of insulin-like growth factor-1 and its major binding protein IGFBP-3. These samples were analyzed at NIEHS in collaboration with Dr. Greg Travlos after extensive laboratory comparision of assay methods. Because levels may be altered by the disease process or treatment, results from prospective analyses are needed to evaluate the association. Procedures and techniques: The case-control study in Los Angeles uses standard case-control methodology. Population controls were enrolled from driver's licence and Medicare lists. The Shanghai study analyses use nested case control studies of incident lung cancer within the prospective cohort. Genotyping is done by PCR based methods. Accomplishments: A number of publications have emerged from the study of genetic polymorphisms and lung cancer risk in African-Americans and Caucasians - 18 to date. In the past year, we have had two manuscripts accepted on DNA repair polymorphisms and lung cancer risk. In the Shanghai cohort study, we have published evidence of a gene-diet interaction between isothiocyanate intake and genetic polymorphisms of GSTM1 and GSTT1 that are involved in their metabolism. Our analysis of IGF-1 and IGF1-BP3 in this cohort represents the first prospective look at this association.