Novel mutational landscapes and expression signatures of lung squamous cell carcinoma.

Donghai Xiong,Hui Jiang,Yuxin Yin,Eva Szabo,Yian Wang,Ming You,Ronald A Lubet,Jing Pan

doi:10.18632/oncotarget.23716

Donghai Xiong, Hui Jiang + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.23716

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Abstract

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.

Highlights

Lung cancer is a major cause of cancer-related deaths worldwide, occurring in more than a million new patients annually [1]
The 16 mouse lung squamous cell carcinoma (LUSC) harbored 5,664 somatic coding mutations that consisted of 2,885 missense, 106 nonsense, 2,426 silent mutations, 167 small insertions and deletions and 80 alterations residing in exonexon boundaries (Supplementary Table 2 [Excel File])
The cancer genes most frequently mutated in the mouse LUSC tumors (≥25%, i.e., mutated in at least 4 samples of 16 tumors) were as follows: Muc4, Prg4, Igf2r, Ctsll3, Dlgap1, Hspa9, Armcx3, Cdk1, Pcdhb15, Fus, Gga1, Il2rb, Kmt2d (Mll2), Mapk6, Myh1, Ncoa3 (Src3), Obscn, Runx2, Zmynd8, Ido1, Nkain2, Pyy, Stil, Tcl1b4, Tfeb, and Trpv1 (Figure 1)

Summary

Introduction

Lung cancer is a major cause of cancer-related deaths worldwide, occurring in more than a million new patients annually [1]. Along with exposure to environmental carcinogens contribute significantly to the risk of developing lung cancer [2]. Non-Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer, comprising 80–85% of all cases. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the two major subtypes of NSCLC, each comprising about 30% of lung cancer diagnosis. The tumor genomics profiles between LUAD and LUSC differed significantly and high heterogeneity was observed within each cancer type [3,4,5]. LUSC is a highly heterogeneous disease that develops via multiple complex steps [7, 8]. Genetic etiology of LUSC has been studied extensively [9,10,11], more research is needed to increase the knowledge base of LUSC and design more effective prevention and therapeutic strategies

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