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

细胞分裂阻断微核测定：肺癌风险的预测生物标志物

• 批准号: 7694368
• 负责人: RANDA A EL-ZEIN
• 金额: $ 13.86万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7694368
• 关键词: 4-nitrophenethyl bromide; Biological Assay; Biological Markers; Cancer Center; Cancer Etiology; Cancer Patient; Carcinogens; Chromosomal Breaks; Chromosome abnormality; Chromosomes; Clinical; Cytogenetics; Cytokinesis; DNA Damage; DNA Sequence Rearrangement; Data; Development; Early Diagnosis; Epidemiologic Studies; Epidemiology; Funding; Gene Amplification; Genetic Predisposition to Disease; Genome; Goals; Human; Image; Individual; Lesion; Lung; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Micronucleus Tests; Molecular; Molecular Cytogenetics; Molecular Epidemiology; Mutagens; Nested Case-Control Study; Nitrosamines; Nuclear; Outcome; Patients; Peripheral Blood Lymphocyte; Pilot Projects; Predisposition; Production; Recurrence; Reporting; Reproduction spores; Resources; Risk; Risk Assessment; Source; Specificity; Specimen; Structure of parenchyma of lung; Surrogate Markers; Testing; Texas; Tissues; Tobacco use; United States; Universities; University of Texas M D Anderson Cancer Center; assay development; base; cancer risk; case control; chromosome loss; cohort; high risk; improved; interstitial; lung carcinogenesis; micronucleus; mortality; novel marker; peripheral blood; population based; repaired; response; telomere; tool; translational study

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.

描述（由申请人提供）：此申请基于德克萨斯大学M. D. Anderson Cancer Center Center（CA555769，M。M. R. R. Spitz，PI）的持续资助的分子流行病学肺癌研究的病例对照招募和标本。当前应用的目的是验证和扩展我们引人注目的初步数据细胞因子块微核（CBMN）测定[一种细胞遗传学生物标志物测量DNA损伤]在人类淋巴细胞中，作为一种生物标志物，作为一种鉴定患有肺癌风险的个体的生物标志物。在一项试点研究中，我们证明了使用烟草特异性亚硝基胺NNK作为挑战诱变者，该测定法作为肺癌风险的生物标志物具有很高的敏感性。在当前的应用中，我们建议在250例和250个对照的较大病例控制设置中确认我们的发现，并探索识别NNK诱导损伤所涉及的特定染色体的可能性。我们将检验以下假设：NNK诱导的CBMN分析是肺癌风险的敏感预测因子，这是由于基因组中特定区域的参与而对肺癌发生至关重要。我们提出以下目的：1）确认我们的初始观察结果表明CBMN分析是识别患有肺癌风险的个体的敏感标记。在另外250例和250个对照中，将测量自发和NNK诱导的染色体损伤。 2.a）使用鱼类探针（pancentromeric，端粒和天空探针），在自发和NNK诱导的细胞遗传学培养物中观察到的异常的特定染色体区域。 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像差的特异性。确认替代标志物代表了目标组织中分子变化的代表，这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评估遗传易感性。该应用的总体目标是将这种强大的测定方法开发为鉴定高风险个体的癌症风险评估工具。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因子块微核测定法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发现，证明该测定法的高灵敏度是肺癌风险的预测指标。然后，我们将探索鉴定在外周血和靶组织中观察到的染色体病变中涉及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开发为鉴定高风险个体的癌症风险评估工具。

项目成果

Chronic obstructive pulmonary disease among lung cancer-free smokers: The importance of healthy controls.

无肺癌吸烟者的慢性阻塞性肺疾病：健康控制的重要性。

• DOI: 10.1016/j.resinv.2017.11.002
• 发表时间: 2018
• 期刊: Respiratory investigation
• 影响因子: 3.1
• 作者: Karpman,MichelleD;Eldridge,Ronald;Follis,JackL;Etzel,CarolJ;Shete,Sanjay;El-Zein,RandaA
• 通讯作者: El-Zein,RandaA