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

描述（由申请人提供）：本申请建立在德克萨斯大学M分校流行病学系正在进行的分子流行病学肺癌研究的病例对照招募和标本资源基础上。D.安德森癌症中心（CA 55769，M. R. Spitz，PI）。当前申请的目标是验证和扩展我们令人信服的初步数据，即人类淋巴细胞中的细胞分裂阻断微核（CBMN）测定[一种测量DNA损伤的细胞遗传学生物标志物]，作为识别肺癌风险个体的生物标志物。在的初步研究中，我们证明了使用烟草特异性亚硝胺NNK作为挑战诱变剂的测定作为肺癌风险生物标志物的高灵敏度。在当前的应用中，我们建议在250例病例和250例对照的较大病例对照设置中证实我们的发现，并探索鉴定参与NNK诱导的损伤的特定染色体的可能性。我们将检验NNK诱导的CBMN测定是肺癌风险的敏感预测因子的假设，这是由于涉及基因组中对肺癌发生至关重要的特定区域。我们提出以下目标：1）证实我们的初步观察，即CBMN测定是鉴定处于发展肺癌风险的个体的敏感标志物。在另外250例病例和250例对照中测量自发和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）确定自发和NNK诱导的细胞遗传学培养物中观察到的畸变产生所涉及的特定染色体区域。2.b）在一部分患者中，我们将使用分子细胞遗传学确定肺组织中这些畸变的特异性。替代标记物代表靶组织中的分子变化的确认对基于人群的分子流行病学研究具有影响，该研究使用替代组织来评估癌症的遗传易感性。本申请的总体目标是允许将这种稳健的测定开发成用于识别高风险个体的癌症风险评估工具。在本研究中，我们建议使用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志物。我们将首先验证我们的初步研究结果，证明这种检测作为肺癌风险预测的高灵敏度。然后，我们将探讨识别外周血和靶组织中观察到的染色体病变所涉及的特定染色体区域的可能性。这种方法将反过来允许将这种测定开发成用于识别高风险个体的癌症风险评估工具。

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.