Xiong Donghai, Pan Jing, Yin Yuxin, Jiang Hui, Szabo Eva, Lubet Ronald A, Wang Yian, You Ming
Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Oncotarget. 2017 Dec 27;9(7):7424-7441. doi: 10.18632/oncotarget.23716. eCollection 2018 Jan 26.
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 and 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 , , and 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.
肺鳞状细胞癌（LUSC）是非小细胞肺癌的主要亚型。为了加深我们对LUSC病理生物学的理解，我们对16个小鼠致癌物诱导的LUSC肿瘤和8个正常小鼠肺组织样本进行了外显子组测序和RNA测序。此外，我们对来自同一小鼠模型的两个独立肿瘤进行了单细胞RNA测序。我们确定了一份在小鼠LUSC肿瘤中反复突变的59个癌症基因清单，其中47个（80%）在人类LUSC中也发生了突变。在单细胞水平上，我们检测到两个LUSC肿瘤各自独特的克隆突变模式，分别由携带突变体和基因的克隆引发。我们还确定了一种表达特征，可作为LUSC肿瘤的有效分类器和肺癌患者生存结果的有力预测指标。最后，我们发现一些突变的LUSC基因与人类LUSC中抑制性免疫检查点基因（如、、和）的肿瘤表达显著改变有关。LUSC的克隆进化、突变图谱和表达特征的新发现为LUSC的整体治疗和免疫治疗提出了新的靶点。
