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

Frontiers in Oncology
Mingming JiaTian Chi

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 ...Continue Reading

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Citations

Jul 3, 2021·International Journal of Molecular Sciences·Sara BravacciniPaola Ulivi

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Methods Mentioned

BETA
RNA-seq

Software Mentioned

CIBERSORT
R package “ maftools
MuTect
GSEA
GraphPad Prism
Xena
R
SignatureAnalyzer
SignatureAnalyzer ” R package

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