High expression of TMEM200A is associated with a poor prognosis and immune infiltration in gastric cancer

Abstract

Background: Gastric cancer (GC) is one of the global malignant tumors with high incidence and poor prognosis. Exploring new GC molecular markers is important to improve GC prognosis. Transmembrane protein 200A (TMEM200A) is a member of the family of transmembrane proteins (TMEM). This study is the first to investigate the potential function of TMEM200A and its relationship with immune infiltration in GC. Methods: The differential expression of TMEM200A was determined through the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The receiver operating characteristic (ROC) curve was drawn to assess the diagnostic value of TMEM200A for GC. The relationship between TMEM200A and the clinical characteristics of patients with GC was investigated using the Wilcoxon test and the Kruskal-Wallis test. The effect of TMEM200A on overall survival (OS) was identified using the Kaplan-Meier method, the Log-rank test, the univariate/multivariate Cox regression analysis, and the nomogram prediction model. The co-expressed genes and gene set enrichment analysis (GSEA) were used to explore the potential biological functions of TMEM200A. We used the Tumor Immune Estimation Resource (TIMER) database and the ssGSEA algorithm to estimate the relationship between TMEM200A and immune cell infiltration. Furthermore, we investigated the correlation of TMEM200A with immune checkpoint/immune cell surface markers using the TCGA-STAD data set. Finally, we identified prognosis-related methylation sites in TMEM200A using MethSurv. Results: TMEM200A was highly expressed in GC tissues. TMEM200A had a good diagnostic value for GC. High expression of TMEM200A may shorten the OS of GC patients and may be an independent risk factor for OS in GC patients. TMEM200A participates in the construction of a predictive model with a good predictive effect on the survival rate of GC patients at 1, 3, and 5 years. Co-expressed genes and GSEA indicated that TMEM200A may be an adhesion molecule closely associated with tumor invasion and metastasis. In addition, TMEM200A may be significantly associated with immune cell infiltration and immune checkpoint expression. We also found that TMEM200A contains three methylation sites associated with a poor prognosis. Conclusion: Upregulated TMEM200A may be a promising prognostic marker for GC and is closely associated with the tumor microenvironment (TME).

Keywords: TMEM200A; bioinformatics; gastric cancer; immune infiltration; prognostic.

FIGURE 1

Pan-cancer analysis of TMEM200A expression levels. (A) Expression of TMEM200A in different kinds of tumor and adjacent tissues in the TIMER database. (B) Expression of TMEM200A in different kinds of tumor and normal tissues from the GEPIA database. *, p < 0.05; **, p < 0.01; ***, p < 0.001.

FIGURE 2

Expression level and diagnostic value of TMEM200A in GC. (A) TMEM200A expression levels in GC tissue (n = 375) and adjacent tissue (n = 32) in the TCGA-STAD data set. (B) Expression levels of TMEM200A in TCGA-STAD GC tissues (n = 413) and GTEx normal gastric tissues (n = 174). (C) TMEM200A expression levels in GC tissues (n = 27) and adjacent tissues (n = 27) of paired samples in the TCGA-STAD dataset. (D) Expression levels of TMEM200A in GC tissues (n = 111) and normal tissues (n = 21) of the GSE54129 dataset. (E) TMEM200A expression levels in GC tissues (n = 100) and normal tissues (n = 300) of the GSE66229 data set. (F) ROC curve of TMEM200A for identifying GC tissues.

FIGURE 3

Correlation between the expression of TMEM200A and the clinical characteristics of patients with GC. TCGA-STAD cohort: (A) alive Status, (B) stage, (C) stage T. GSE15459 cohort: (D) alive Status, (E) gender, (F) Lauren-Classification, (G) Subtype.

FIGURE 4

Analysis of the prognostic value of TMEM200A in GC. (A) Kaplan-Meier curves for OS of patients in the TCGA-STAD cohort. (B) Kaplan-Meier curves for OS of patients in the GSE15459 cohort. (C) Forest plot of the results of the TCGA-STAD cohort multifactorial Cox regression analysis. (D) Forest plot of the results of the multifactorial Cox regression analysis of the GSE15459 cohort.

FIGURE 5

Nomogram plots of combining TMEM200A and clinical features evaluated survival in GC. (A) Nomogram for predicting OS in TCGA-STAD dataset. (B) Nomogram for predicting OS in the GSE15459 dataset. (C–E) The calibration curve of the nomogram for one, three, and 5 years of OS prediction in TCGA-STAD dataset. (F–H) The calibration curve of the nomogram for one, three, and 5 years of OS prediction in GSE15459 dataset.

FIGURE 6

Co-expression of genes and functional enrichment of TMEM200A. (A) Volcano map of 8492 co-expressed genes of TMEM200A. (B) Heat map of the top 50 TMEM200A negatively related genes. (C) Heat map of the top 50 TMEM200A positively related genes. (D) GO enrichment analysis. (E) KEGG enrichment analysis.

FIGURE 7

Results of the GSEA analysis of TMEM200A. (A) GSEA of GO. (B) GSEA of KEGG.

FIGURE 8

Results of TMEM200A and tumor immunological correlation analysis. (A) Correlation analysis of TMEM200A with the level of infiltration of six types of immune cells in the TIMER database. (B) Correlation analysis of TMEM200A with 28 immune cell subtypes calculated using the ssGSEA algorithm. (C) Correlation analysis of TMEM200A and immune checkpoint expression.

FIGURE 9

Correlation between the expression level of TMEM200A and the IC50 of chemotherapy drugs. (A) AKT.inhibitor.VIII, (B) Afatinib, (C) Gefitinib, (D) Lapatinib, (E) Metformin, (F) All-trans Retinoic Acid, (G) Cytarabine, (H) Nilotinib, and (I) Crizotinib.

FIGURE 10

DNA methylation sites of TMEM200A. (A) Red to blue means that the methylation level goes from high to low. The different colored boxes represent ethnicity, race, age, event, relation to UCSC CpG Island, and UCSC RefGene Group. (B) The Kaplan-Meier curve of TMEM200A-TSS200-Open_Sea-cg02769951 in patients with GC. (C) The Kaplan-Meier curve of TMEM200A-5′UTR; 1stExon-Open_Sea-cg18172186 in patients with GC. (D) The Kaplan-Meier curve of TMEM200A-TSS200-Open_Sea-cg27384002 in patients with GC.