Novel mutational landscapes and expression signatures of lung squamous cell carcinoma
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Donghai Xiong1,2, Jing Pan1,2, Yuxin Yin1,2, Hui Jiang1,2, Eva Szabo3, Ronald A. Lubet3, Yian Wang1,2 and Ming You1,2
1Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
2Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
3Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD 20850, USA
Ming You, email: [email protected]
Keywords: LUSC (lung squamous cell carcinoma); tumor evolution; somatic mutation; expression signature; immunotherapy
Received: October 29, 2017 Accepted: November 26, 2017 Published: December 27, 2017
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.
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