Five EMT-related genes signature predicts overall survival and immune environment in microsatellite instability-high gastric cancer

Background Microsatellite instability-high (MSI-H) subgroup of gastric cancer (GC) is characterized by a high tumor mutational burden, increased lymphocytic infiltration, and enhanced inflammatory cytokines. GC patients with MSI-H status have a good response to immune checkpoint blockade management. However, heterogeneity within the subtype and the underlying mechanisms of shaping tumor microenvironments remain poorly understood. Methods RNA expression levels and clinical parameters of GC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The data were analyzed using single-sample Gene Set Enrichment Analysis (ssGSEA), univariate Cox regression, multivariate Cox regression, and Least Absolute Shrinkage Selection Operator (LASSO) regression. In addition, multiplex immunohistochemistry (mIHC) was used in our clinical cohort for the tumor microenvironment study. Results By ssGSEA and survival analysis, the EMT signaling pathway was identified as a representative pathway, which can stratify the patients with MSI-H GC with significant survival predictive power. Then, a novel representative EMT-related five-gene signature (namely CALU, PCOLCE2, PLOD2, SGCD, and THBS2) was established from EMT signaling gene set, which sensitivity and specificity were further validated in the independent GEO database (GSE62254) cohort for disease outcome prediction. Based on public single-cell data and in situ immunohistochemistry, we found that most of these five genes were abundantly expressed in cancer-associated fibroblasts. Furthermore, patients with high or low risk divided by this five-gene signature exhibited a strong correlation of the distinct patterns of tumor immune microenvironment. By mIHC staining of sections from 30 patients with MSI-H status, we showed that the patients with better prognoses had the increased infiltration of CD8(+) cells in the primary tumoral tissue. Conclusion Our study developed a simple five-gene signature for stratifying MSI-H GC patients with survival predictive power.

Automated summary

This study identified the EMT signaling pathway as a representative pathway for predicting the survival of MSI-H gastric cancer (GC) patients. A novel five-gene signature (CALU, PCOLCE2, PLOD2, SGCD, and THBS2) was established from the EMT signaling gene set for disease outcome prediction. The five genes were found to be abundantly expressed in cancer-associated fibroblasts, and patients with different risk groups based on the five-gene signature showed distinct patterns of tumor immune microenvironment.