Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-02-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.00168/full |
| _version_ | 1818014574718222336 |
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| author | Mingming Jia Mingming Jia Mingming Jia Linli Yao Qin Yang Tian Chi Tian Chi |
| author_facet | Mingming Jia Mingming Jia Mingming Jia Linli Yao Qin Yang Tian Chi Tian Chi |
| author_sort | Mingming Jia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T06:47:11Z |
| format | Article |
| id | doaj.art-fc1c046bbc1743949f4e8bdf28954a54 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-14T06:47:11Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-fc1c046bbc1743949f4e8bdf28954a542022-12-22T02:07:09ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-02-011010.3389/fonc.2020.00168508448Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung AdenocarcinomaMingming Jia0Mingming Jia1Mingming Jia2Linli Yao3Qin Yang4Tian Chi5Tian Chi6School of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaCAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaDepartment Immunobiology, Yale University School of Medicine, New Haven, CT, United StatesImmune 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.https://www.frontiersin.org/article/10.3389/fonc.2020.00168/fulllung adenocarcinomaMSH2 expressionbiomarkersimmunotherapytumor mutation burden |
| spellingShingle | Mingming Jia Mingming Jia Mingming Jia Linli Yao Qin Yang Tian Chi Tian Chi Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma Frontiers in Oncology lung adenocarcinoma MSH2 expression biomarkers immunotherapy tumor mutation burden |
| title | Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma |
| title_full | Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma |
| title_fullStr | Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma |
| title_full_unstemmed | Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma |
| title_short | Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma |
| title_sort | association of msh2 expression with tumor mutational burden and the immune microenvironment in lung adenocarcinoma |
| topic | lung adenocarcinoma MSH2 expression biomarkers immunotherapy tumor mutation burden |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.00168/full |
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