Detecting the Presence and Progression of Premalignant Lung Lesions via Airway Gene Expression.
Detecting the Presence and Progression of Premalignant Lung Lesions via Airway Gene Expression.
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DOI：
10.1158/1078-0432.ccr-16-2540
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发表时间：
2017-09-01
期刊：
影响因子：
--
通讯作者：
Spira AE
中科院分区：
文献类型：
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作者：
Beane J;Mazzilli SA;Tassinari AM;Liu G;Zhang X;Liu H;Buncio AD;Dhillon SS;Platero SJ;Lenburg ME;Reid ME;Lam S;Spira AE
肺癌(LC)是美国癌症死亡的主要原因。疾病发生前的分子事件知之甚少，也没有有效的工具来识别患有将进展为浸润性癌症的癌前病变(PML)的吸烟者。先前的工作证实了与LC相关的烟雾暴露的呼吸道损伤区域中的分子变化。在这里，我们将重点放在疾病过程的早期阶段，利用损伤的呼吸道领域来研究PMLS及其在LC化学预防中的作用。对50例PML患者和25例非PML患者的正常支气管黏膜上皮细胞进行了mRNA-Seq分析。使用替代变量和基因集浓缩分析，我们确定了有无PML受试者之间差异表达的基因、途径和LC相关基因集。开发了一种计算管道来建立和测试与化学预防相关的生物标记物。我们在呼吸道领域发现了280个与PML相关的基因。在上调的基因中，氧化磷酸化强烈丰富，免疫组织化学和生物能量学研究证实了PML的通路发现。使用已发表的LC数据集也证实了与PML和鳞状细胞癌(SCC)的关系。该生物标记物能很好地预测PMLS的存在(AUC=0.92，n=17)，以及PMLS进展/稳定与消退相关的生物标记物评分的变化(AUC=0.75，n=51)。患有PML的吸烟者气道场的转录改变反映了代谢和早期肺SCC的改变，可能被用来对PML进展的高危吸烟者进行分层，并监测化学预防试验的结果。
Lung cancer (LC) is the leading cause of cancer death in the US. The molecular events preceding the onset of disease are poorly understood and no effective tools exist to identify smokers with premalignant lesions (PMLs) that will progress to invasive cancer. Prior work identified molecular alterations in the smoke-exposed airway field of injury associated with LC. Here we focus on an earlier stage in the disease process leveraging the airway field of injury to study PMLs and its utility in LC chemoprevention. Bronchial epithelial cells from normal appearing bronchial mucosa were profiled by mRNA-Seq from subjects with (n=50) and without (n=25) PMLs. Using surrogate variable and gene set enrichment analysis we identified genes, pathways, and LC-related gene sets differentially expressed between subjects with and without PMLs. A computational pipeline was developed to build and test a chemoprevention-relevant biomarker. We identified 280 genes in the airway field associated with the presence of PMLs. Among the up-regulated genes, oxidative phosphorylation was strongly enriched and immunohistochemistry and bioenergetics studies confirmed pathway findings in PMLs. The relationship to PMLs and squamous cell carcinomas (SCC) was also confirmed using published LC datasets. The biomarker performed well predicting the presence of PMLs (AUC=0.92, n=17), and changes in the biomarker score associated with progression/stability vs. regression of PMLs (AUC=0.75, n=51). Transcriptomic alterations in the airway field of smokers with PMLs reflect metabolic and early lung SCC alterations and may be leveraged to stratify smokers at high-risk for PML progression and monitor outcome in chemoprevention trials.