Cytokinesis-blocked micronucleus assay: a predictive biomarker of lung cancer ris

描述(由申请人提供)：本申请基于德克萨斯大学安德森癌症中心流行病学系(CA55769，M.R.Spitz，PI)正在进行的一项分子流行病学肺癌研究的病例对照招募和标本来源。目前应用程序的目标是验证和扩展我们令人信服的初步数据-胞质分裂阻断微核(CBMN)分析[一种测量DNA损伤的细胞遗传学生物标记物]，作为识别肺癌风险个人的生物标记物。在的一项初步研究中，我们使用烟草特有的亚硝胺NNK作为激发诱变剂，证明了该方法作为肺癌风险生物标志物的高敏感性。在目前的应用中，我们建议在250例病例和250名对照的更大病例对照环境中证实我们的发现，并探索识别与NNK诱导的损伤有关的特定染色体的可能性。我们将检验这样一种假设，即NNK诱导的CBMN检测是肺癌风险的敏感预测因子，因为涉及到基因组中对肺癌发生至关重要的特定区域。我们提出了以下目标：1)证实我们的初步观察表明，CBMN检测是一种敏感的标记物，用于识别有患肺癌风险的个体。在另外250名患者和250名对照中，将测量自发的和NNK诱导的染色体损伤。2.a)使用FISH探针(泛着丝粒、端粒和Sky探针)确定在自发和NNK诱导的细胞遗传学培养中与所观察到的畸变产生有关的特定染色体区域。2.b)在一组患者中，我们将使用分子细胞遗传学在肺组织中确定这些异常的特异性。证实替代标记代表靶组织中的分子变化，这对基于人群的分子流行病学研究具有重要意义，该研究使用替代组织来评估癌症的遗传易感性。这项应用的总体目标是使这一强大的检测方法发展成为一种癌症风险评估工具，用于识别高危个体。在目前的研究中，我们建议测试烟草特异性亚硝胺诱导的胞质分裂阻断微核试验作为肺癌风险评估的新标记物的使用。我们将首先验证我们的初步发现，证明这项检测作为肺癌风险预测指标的高度敏感性。然后，我们将探索在外周血液和目标组织中观察到的染色体损伤所涉及的特定染色体区域的识别可能性。这种方法反过来将使这一检测方法发展成为一种癌症风险评估工具，用于识别高危个体。

DESCRIPTION (provided by applicant): This application builds upon the case-control recruitment and specimen recourses of an ongoing funded molecular epidemiology lung cancer study in the Department of Epidemiology at the University of Texas M. D. Anderson Cancer Center (CA55769, M. R. Spitz, PI). The goal of the current application is to validate and extend our compelling preliminary data the Cytokinesis-block micronucleus (CBMN) assay [a cytogenetic biomarker measuring DNA damage] in human lymphocytes as a biomarker for identification of individuals at risk of lung cancer. In a pilot study of, we demonstrated the high sensitivity of the assay as biomarker of risk of lung cancer using the tobacco-specific nitrosamine NNK as a challenge mutagen. In the current application, we propose to confirm our findings in a larger case control setting of 250 cases and 250 controls, and to explore the possibility of identifying the specific chromosomes involved in the NNK-induced damage. We will test the hypothesis that NNK-induced CBMN assay is a sensitive predictor of lung cancer risk due to involvement of specific regions in the genome that are critical for lung carcinogenesis. We propose the following aims: 1) To confirm our initial observation indicating that the CBMN assay is a sensitive marker for identifying individuals at risk of developing lung cancer. Both spontaneous and NNK- induced chromosome damage will be measured in an additional 250 cases and 250 controls. 2.a) To determine the specific chromosome regions involved in the production of the observed aberrations in both spontaneous and NNK-induced cytogenetic cultures using FISH probes (pancentromeric, telomeric and SKY probes). 2.b) In a subset of patients, we will then determine the specificity of these aberrations using molecular cytogenetics, in lung tissues. Confirmation that surrogate markers are representative of molecular changes in the target tissue has implications for population-based molecular epidemiologic research that uses surrogate tissues to evaluate genetic susceptibility to cancer. The overall goal of this application is to allow the development of this robust assay into a cancer risk assessment tool for identification of high-risk individuals. In the current study we propose to test the use of the tobacco-specific nitrosamine induced Cytokinesis-block micronucleus assay as a novel marker for lung cancer risk assessment. We will first validate our initial findings demonstrating the high sensitivity of this assay as a predictor of lung cancer risk. We will then explore the possibility of identifying the specific chromosome regions involved in the chromosome lesions observed in peripheral blood and in target tissues. This approach will in turn allow the development of this assay into a cancer risk assessment tool for identification of high-risk individuals.