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 MD 安德森癌症中心流行病学系正在进行的资助的分子流行病学肺癌研究的病例对照招募和样本资源的基础上（CA55769，M. R. Spitz，PI）。当前应用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。在一项初步研究中，我们使用烟草特异性亚硝胺 NNK 作为诱变剂，证明了该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 例对照的更大病例对照环境中证实我们的发现，并探索鉴定参与 NNK 诱导损伤的特定染色体的可能性。我们将检验以下假设：NNK 诱导的 CBMN 检测是肺癌风险的敏感预测因子，因为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结果表明 CBMN 检测是识别有患肺癌风险的个体的敏感标记。将在另外 250 个病例和 250 个对照中测量自发性和 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涉及产生观察到的畸变的特定染色体区域。 2.b) 在一部分患者中，我们将使用分子细胞遗传学在肺组织中确定这些畸变的特异性。确认替代标记代表目标组织中的分子变化，对于使用替代组织评估癌症遗传易感性的基于人群的分子流行病学研究具有重要意义。该应用程序的总体目标是将这种强大的检测方法开发成癌症风险评估工具，以识别高风险个体。在当前的研究中，我们建议测试烟草特异性亚硝胺诱导的细胞分裂微核测定作为肺癌风险评估的新标记物的用途。我们将首先验证我们的初步发现，证明该测定作为肺癌风险预测因子的高灵敏度。然后，我们将探索识别与外周血和靶组织中观察到的染色体病变有关的特定染色体区域的可能性。这种方法反过来将使该测定法发展成为一种癌症风险评估工具，用于识别高风险个体。

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.