Airway gene expression in smokers: an early diagnostic biomarker for lung cancer

吸烟者气道基因表达：肺癌的早期诊断生物标志物

• 批准号: 7776874
• 负责人: Avrum E Spira
• 金额: $ 30.88万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7776874
• 关键词: Age; Algorithms; Biological Markers; Biopsy; Bronchi; Bronchoscopy; Cancer Etiology; Cells; Cessation of life; Clinical; Clinical Data; Collaborations; Computational algorithm; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Drug Metabolic Detoxication; Early Diagnosis; Effectiveness; Engineering; Enzymes; Epigenetic Process; Epithelial; Epithelial Cells; Evaluation; Excision; Gene Expression; Gene Expression Profile; Genetic; Goals; Histologic; Interdisciplinary Study; Ireland; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Medical center; Modeling; Molecular Profiling; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oligonucleotide Microarrays; Operative Surgical Procedures; Outcome; Patients; Pattern; Play; Population; Predictive Value; Probability; Pulmonary Mass; Recruitment Activity; Research Personnel; Risk; Risk Factors; Role; Sampling; Screening procedure; Smoker; Smoking History; Staging; Testing; Therapeutic; Tobacco; Tobacco smoke; Toxin; United States; Voting; Weight; Woman; Work; airway epithelium; base; cell injury; cell type; cigarette smoking; clinically relevant; cohort; computerized tools; disease diagnosis; disorder subtype; experience; innovation; lung carcinogenesis; men; minimally invasive; mortality; non-smoker; novel; predictive modeling; programs; research clinical testing; response; tool

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in both men and women in the United States. The high mortality in patients with lung cancer results, in part, from the lack of effective tools to diagnose the disease at an early stage before it has spread to regional nodes or has metastasized beyond the lung. Our long-term goal is to develop a relatively noninvasive means of assessing the degree of airway epithelial cell damage and the risk for having or developing lung cancer among smokers. The objective of this application is to develop an intrathoracic (mainstem bronchus) airway gene expression profile capable of serving as an early diagnostic biomarker for lung cancer in smokers with clinical suspicion of disease. This approach is based on the hypothesis that patterns of gene expression in the histologically normal airway epithelium of a smoker reflect the types and degree of damage induced by the tobacco smoke and can predict that smoker's risk for having lung cancer. Using oligonucleotide microarrays, we have identified a gene expression signature in histologically normal large airway epithelial cells obtained at bronchoscopy that can serve as a highly sensitive and specific biomarker for distinguishing smokers with and without lung cancer. In this proposal, we will 1) validate this diagnostic airway biomarker in a large independent cohort of smokers with suspicion for lung cancer; 2) evaluate our biomarker's accuracy in predicting the presence of lung cancer in stage 1 disease; 3) integrate airway gene expression profiles with established clinical risk factors for disease to produce a clinicogenomic predictive model that can guide patient evaluation and management; 4) develop a second gene expression signature in normal airway epithelium capable of distinguishing small cell vs. non-small cell lung cancer using novel reverse engineering algorithms. These studies will produce a relatively noninvasive tool effective in diagnosing lung cancer at an early and potentially curable stage. These gene expression-based biomarkers may eliminate the need for additional and often more invasive diagnostic tests that are costly, incur risk, and prolong the diagnostic evaluation of smokers with suspicion of lung cancer.

描述（由申请人提供）：肺癌是美国男性和女性癌症死亡的主要原因。肺癌患者的高死亡率部分是由于缺乏有效的工具来诊断该疾病的早期阶段，然后再传播到区域淋巴结或已转移到肺部以外。我们的长期目标是开发一种评估气道上皮细胞损害程度以及吸烟者患肺癌或患肺癌的风险的相对无创方法。该应用的目的是开发胸腔内（主要的支气管）气道基因表达谱，能够作为临床怀疑疾病的吸烟者的早期诊断生物标志物。这种方法基于以下假设：吸烟者的组织学正常气道上皮中基因表达的模式反映了烟草烟雾引起的损害的类型和程度，并且可以预测吸烟者患肺癌的风险。使用寡核苷酸微阵列，我们已经确定了在支气管镜检查中获得的组织学正常气道上皮细胞中的基因表达特征，该基因表达可以用作具有和没有肺癌的吸烟者的高度敏感和特异性生物标志物。在此提案中，我们将1）验证这种诊断气道生物标志物，以众多独立的吸烟者对肺癌的怀疑； 2）评估我们的生物标志物在预测1期疾病中肺癌存在方面的准确性； 3）将气道基因表达谱与疾病的临床风险因素相结合，以产生可以指导患者评估和管理的临床基因组预测模型； 4）在正常气道上皮中开发第二个基因表达特征，能够使用新型的反向工程算法区分小细胞与非小细胞肺癌。这些研究将产生一个相对无创的工具，可在早期且可能可治愈的阶段诊断肺癌。这些基于基因表达的生物标志物可能会消除对昂贵，风险高昂的额外侵入性诊断测试的需求，并延长对涉嫌肺癌的吸烟者的诊断评估。