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

Abstract

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.

Analysis of the Expression and Prognostic Value of MSH2 in Pan-Cancer Based on Bioinformatics

“…Existing evidence showed that MSH2 is overexpressed in pancreatic cancer cells and can be used as a CD4+ helper T cell antigens for the immunotherapy of patients with pancreatic cancer [ 33 ]. In LUAD, high expression of MSH2 was significantly correlated with CD8+ T cell infiltration [ 34 ]. In addition, the loss of MMR protein expression was related to the selective downregulation of human leukocyte antigen class I antigens, which contributes to the immune escape of endometrial carcinomas [ 35 ].…”

“…TMB is a promising biomarker for pan-cancer prediction, leading immunotherapy into the era of precision medicine [ 36 ]. In LUAD, the increase in MSH2 expression was significantly positively correlated with TMB [ 34 ]. Studies have shown that high nonsynonymous TMB was a good prognostic factor for patients with non-small-cell lung cancer [ 37 ].…”

Exploration of the role of tumor mutation burden in clinical significance, immunotherapy response predictor and immune cell infiltration in colon cancer

“…Somatic mutations lead to a change in amino aicds which may increase the number of neo-antigens theoretically, which could activate the immune system and strengthen the immune cell in ltration. The change in immune microenvironment could affect immunotherapy response and have an impact of prognosis in patients with different cancers [25][26][27][28] . Based on these, TMB is becoming a hot biomarker for various cancers [29][30][31][32][33][34][35][36] .…”

Integrated Analysis of Distant Metastasis-Associated Genes and Potential Drugs in Colon Adenocarcinoma

“…Subsequently, to evaluate the prognostic value of risk score, we drew the ROC curve at 5 years of OS and calculated the AUC value. From Supplementary Figure 1B, the 5 year AUC was 0.672 (AUC > 0.65), which revealed superior predictive accuracy in OS (19). Second, for the individual genes, the correlations between their expression levels and prognosis are shown in Figure 6.…”