Boston University School of Medicine, Boston, MA, 02118, USA.
David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
Nat Commun. 2019 Apr 23;10(1):1856. doi: 10.1038/s41467-019-09834-2.
Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer.
支气管癌前病变（PML）是肺鳞状细胞癌的前体，但结局各异，我们缺乏识别和治疗有进展为癌症风险的 PML 的工具。本研究通过对高危吸烟者的支气管内活检进行 RNA-Seq 分析，报告了基于上皮和免疫过程的四个分子亚型 PML 的鉴定。增殖型亚型富含支气管发育不良，并表现出代谢和细胞周期途径的上调。增殖型 PML 相关基因特征可从正常外观的未受累大气道刷片中以高特异性识别具有增殖型 PML 的受试者。在进展/持续增殖性病变中，干扰素信号和抗原加工/呈递途径的表达减少，免疫荧光显示与退行性病变相比，固有和适应性免疫细胞耗竭。在 PML 或未受累气道中测量的分子生物标志物可增强组织病理学分级，并提示免疫预防策略以阻断 PML 向肺癌的进展。
