Novel mutational landscapes and expression signatures of lung squamous cell carcinoma.
Novel mutational landscapes and expression signatures of lung squamous cell carcinoma.
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DOI：
10.18632/oncotarget.23716
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发表时间：
2018-01-26
期刊：
影响因子：
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通讯作者：
You M
中科院分区：
文献类型：
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作者：
Xiong D;Pan J;Yin Y;Jiang H;Szabo E;Lubet RA;Wang Y;You M
肺鳞癌(LUSC)是非小细胞肺癌的主要亚型。为了加深对LUSC病理生物学的了解，我们对16例小鼠致癌物诱发的LUSC肿瘤和8例正常小鼠肺组织进行了外显子组测序和RNA-SEQ分析。此外，我们对来自同一小鼠模型的两个独立的肿瘤进行了单细胞RNA-SEQ。我们确定了59个在小鼠LUSC肿瘤中反复突变的癌症基因，其中47个(80%)在人类LUSC中也发生了突变。在单细胞水平上，我们检测到了两个LUSC肿瘤各自独特的克隆性突变模式，分别从携带突变的IGFBP7和Trp53基因的克隆开始。我们还确定了一个表达特征，作为LUSC肿瘤的有效分类器，并强烈预测肺癌患者的生存结果。最后，我们发现一些突变的LUSC基因与人LUSC中抑制性免疫检查点基因如PD-L1、VistA、TIM3和LAG3的肿瘤表达显著变化有关。LUSC的克隆进化、突变情况和表达特征的新发现为LUSC的整体治疗和免疫治疗提供了新的靶点。
Lung squamous cell carcinoma (LUSC) is a major subtype of Non-Small Cell Lung Cancer. To increase our understanding of the LUSC pathobiology, we performed exome sequencing and RNA-seq in 16 murine carcinogen-induced LUSC tumors and 8 normal murine lung tissue samples. Additionally, we conducted single-cell RNA-seq on two independent tumors from the same murine model. We identified a list of 59 cancer genes recurrently mutated in the mice LUSC tumors, 47 (80%) of which were also mutated in human LUSCs. At the single cell level, we detected unique clonal mutation patterns for each of the two LUSC tumors, being initiated from clones carrying the mutant Igfbp7 and Trp53 genes, respectively. We also identified an expression signature serving as an effective classifier for LUSC tumors and a strong predictor of survival outcomes of lung cancer patients. Lastly, we found that some of the mutant LUSC genes were associated with the significantly altered tumoral expression of inhibitory immune checkpoint genes such as PD-L1, VISTA, TIM3 and LAG3 in human LUSCs. The novel findings of clonal evolution, mutational landscapes and expression signatures of LUSC suggested new targets for the overall LUSC therapy and the immunotherapy of LUSC.