The Airway Transcriptome as a Biomarker for 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。虽然吸烟是肺癌的主要原因，但只有10-20%的重度吸烟者患肺癌。由于缺乏有效的生物标志物，并且无法确定哪些现在和以前的吸烟者患癌症的风险最大，肺癌通常在扩散后的晚期才被诊断出来；肺癌的5年死亡率为85%，这一数字在过去的30 - 40年里几乎没有变化。该项目的目标是利用气道基因表达谱来开发一种相对非侵入性的方法来评估患烟草相关肺癌的风险。我们的方法基于这样的概念，即香烟烟雾影响整个呼吸道的气道上皮细胞，从而产生气道上皮细胞“场缺陷”，这定义了对烟草烟雾反应的个体差异，并区分吸烟者是否患有肺癌。利用寡核苷酸基因表达阵列，本研究将对有或无肺癌的吸烟者通过刷胸内（大叶支气管）气道获得的上皮细胞的基因表达模式进行表征。肺癌对气道转录组的影响将被定义，以及影响肺癌吸烟者上皮细胞损伤的性别和种族因素。使用多种分类预测算法，胸内上皮基因表达谱可用于预测哪些吸烟者患有肺癌。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in both men and women in the US. While cigarette smoking is the major cause of lung cancer, only 10-20% of heavy smokers develop lung cancer. Because of the lack of effective biomarkers and the inability to identify which current and former smokers are at the greatest risk for developing cancer, lung cancer is most often diagnosed at a late state after it has spread; the five year mortality of lung cancer is 85%, a figure that has changed little over the past 3-4 decades. The goal of this project is to use airway gene expression profiles to develop a relatively non-invasive method for assessing risk of having tobacco-associated lung cancer. Our approach is based on the concept that cigarette smoke affects airway epithelial cells throughout the respiratory tract, thus producing an airway epithelial cell "field defect" that defines individual variations in the response to tobacco smoke and differentiates smokers with and without lung cancer. Using oligonucleotide gene expression arrays, experiments in this proposal will characterize the patterns of gene expression in epithelial cells obtained by brushing intrathoracic (lobar bronchi) airway in smokers with and without lung cancer. The impact of lung cancer on the airway transcriptome will be defined, along with gender and racial factors that influence epithelial cell damage in smokers with lung cancer. Using a number of class prediction algorithms, intrathoracic epithelial gene expression profiles that can be used to predict which smokers have lung cancer will be identified. Competitive PCR and matrix-assisted laser desorption ionization, time-of-flight, mass spectrometry will be used to confirm differential expression of selected genes identified in the array experiments. The long term objective of this study is to develop a non-invasive biomarker for lung cancer that can be tested in subsequent clinical trials to determine its value in identifying that subset of smokers who have, or are at risk for developing lung cancer.