Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma

doi:10.3389/fonc.2020.00168

	Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma
	Jia, Mingming1,2,3 ; Yao, Linli 4; Yang, Qin 4; Chi, Tian1,5
	2020-02-21
发表期刊	FRONTIERS IN ONCOLOGY
ISSN	2234-943X
卷号	10
发表状态	已发表
DOI	10.3389/fonc.2020.00168
摘要	Immune checkpoint blockade (ICB) therapies that target programmed cell death 1 (PD1) and PD1 ligand 1 (PDL1) have demonstrated promising benefits in lung adenocarcinoma (LUAD), and tumor mutational burden (TMB) is the most robust biomarker associated with the efficacy of PD-1-PD-L1 axis blockade in LUAD, but the assessment of TMB by whole-exome sequencing (WES) is rather expensive and time-consuming. Although targeted panel sequencing has been developed and approved by the US Food and Drug Administration (FDA) to estimate TMB, we found that its predictive accuracy for ICB response was significantly lower than WES in LUAD. Given that previous studies were mainly focusing on genomic variations to explore surrogate biomarkers of TMB, we turned to examine the transcriptome-based correlation with TMB in this study. Combining three immunotherapeutic cohorts with two independent The Cancer Genome Atlas (TCGA) datasets, we revealed that the expression of mutS homolog 2 (MSH2), one of the most crucial genes involved in DNA mismatch repair (MMR) pathway, was the strongest feature associated with increased TMB in multivariate analysis. Furthermore, MSH2 expression also displayed a significantly positive correlation with smoking signature while an inverse association with MMR deficiency (MMRd) signature in LUAD. More importantly, high expression of MSH2 markedly correlated with increased PD-L1 expression and CD8+ T cell infiltration, both suggesting a prominent immunotherapy-responsive microenvironment in LUAD. Notably, detecting MSH2 expression is much easier, faster, and cheaper than TMB in clinical practice. Taken together, this study demonstrates the association of MSH2 expression with TMB and the immune microenvironment in LUAD. MSH2 expression may be developed as a potential surrogate biomarker of TMB to identify ICB responders in LUAD.
关键词	lung adenocarcinoma MSH2 expression biomarkers immunotherapy tumor mutation burden
URL	查看原文
收录类别	SCI ; SCIE
语种	英语
WOS研究方向	Oncology
WOS类目	Oncology
WOS记录号	WOS:000524717600001
出版者	FRONTIERS MEDIA SA
WOS关键词	MLH1 PROMOTER METHYLATION ; PD-1 BLOCKADE ; MICROSATELLITE INSTABILITY ; CANCER-IMMUNOTHERAPY
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/119385
专题	生命科学与技术学院_博士生生命科学与技术学院_PI研究组_池天组
通讯作者	Yang, Qin; Chi, Tian
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.Shanghai Jiao Tong Univ, Shanghai Canc Inst, Sch Med, Ren Ji Hosp,State Key Lab Oncogenes & Related Gen, Shanghai, Peoples R China 5.Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Jia, Mingming,Yao, Linli,Yang, Qin,et al. Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma[J]. FRONTIERS IN ONCOLOGY,2020,10.
APA	Jia, Mingming,Yao, Linli,Yang, Qin,&Chi, Tian.(2020).Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma.FRONTIERS IN ONCOLOGY,10.
MLA	Jia, Mingming,et al."Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma".FRONTIERS IN ONCOLOGY 10(2020).