The Graduate Program in Bioinformatics, Boston University, Boston, Massachusetts.
Section of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts.
Cancer Prev Res (Phila). 2017 Nov;10(11):651-659. doi: 10.1158/1940-6207.CAPR-17-0098. Epub 2017 Sep 6.
We have previously shown that gene expression alterations in normal-appearing bronchial epithelial cells can serve as a lung cancer detection biomarker in smokers. Given that miRNAs regulate airway gene expression responses to smoking, we evaluated whether miRNA expression is also altered in the bronchial epithelium of smokers with lung cancer. Using epithelial brushings from the mainstem bronchus of patients undergoing bronchoscopy for suspected lung cancer (as part of the AEGIS-1/2 clinical trials), we profiled miRNA expression via small-RNA sequencing from 347 current and former smokers for which gene expression data were also available. Patients were followed for one year postbronchoscopy until a final diagnosis of lung cancer ( = 194) or benign disease ( = 153) was made. Following removal of 6 low-quality samples, we used 138 patients (AEGIS-1) as a discovery set to identify four miRNAs (miR-146a-5p, miR-324-5p, miR-223-3p, and miR-223-5p) that were downregulated in the bronchial airway of lung cancer patients (ANOVA < 0.002, FDR < 0.2). The expression of these miRNAs is significantly more negatively correlated with the expression of their mRNA targets than with the expression of other nontarget genes (K-S < 0.05). Furthermore, these mRNA targets are enriched among genes whose expression is elevated in cancer patients (GSEA FDR < 0.001). Finally, we found that the addition of miR-146a-5p to an existing mRNA biomarker for lung cancer significantly improves its performance (AUC) in the 203 samples (AEGIS-1/2) serving an independent test set (DeLong < 0.05). Our findings suggest that there are miRNAs whose expression is altered in the cytologically normal bronchial epithelium of smokers with lung cancer, and that they may regulate cancer-associated gene expression differences. .
我们之前已经证明，正常支气管上皮细胞中的基因表达改变可以作为吸烟者肺癌检测的生物标志物。鉴于 miRNA 调节气道对吸烟的基因表达反应，我们评估了肺癌吸烟者的支气管上皮细胞中 miRNA 的表达是否也发生了改变。使用支气管镜检查疑似肺癌患者（作为 AEGIS-1/2 临床试验的一部分）的主支气管上皮刷取物，我们通过小 RNA 测序对 347 名目前和以前的吸烟者的 miRNA 表达进行了分析，这些患者的基因表达数据也可用。患者在支气管镜检查后一年进行随访，直到最终诊断为肺癌（=194）或良性疾病（=153）。去除 6 个低质量样本后，我们使用 138 名患者（AEGIS-1）作为发现集来鉴定 4 个 miRNA（miR-146a-5p、miR-324-5p、miR-223-3p 和 miR-223-5p），这些 miRNA 在肺癌患者的支气管气道中下调（ANOVA<0.002，FDR<0.2）。这些 miRNA 的表达与它们的 mRNA 靶标的表达比与其他非靶基因的表达更显著负相关（K-S<0.05）。此外，这些 mRNA 靶标富集在癌症患者中表达上调的基因中（GSEA FDR<0.001）。最后，我们发现，将 miR-146a-5p 添加到现有的肺癌 mRNA 生物标志物中，可以显著提高其在 203 个样本（AEGIS-1/2）中的性能（AUC）（DeLong<0.05）。我们的研究结果表明，有一些 miRNA 在肺癌吸烟者的细胞学正常支气管上皮细胞中表达改变，并且它们可能调节与癌症相关的基因表达差异。
