Illustrating the biological functions and diagnostic value of transmembrane protein family members in glioma.

Abstract

It is well-established that patients with glioma have a poor prognosis. Although the past few decades have witnessed unprecedented medical advances, the 5-year survival remains dismally low. This study aims to investigate the role of transmembrane protein-related genes in the development and prognosis of glioma and provide new insights into the pathogenesis of the disease. The datasets of glioma patients, including RNA sequencing data and relative clinical information, were obtained from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and Gene Expression Omnibus (GEO) databases. Prognostic transmembrane protein-related genes were identified by univariate Cox analysis. New disease subtypes were recognized based on the consensus clustering method, and their biological uniqueness was verified via various algorithms. The prognosis signature was constructed using the LASSO-Cox regression model, and its predictive power was validated in external datasets by receiver operating characteristic (ROC) curve analysis. An independent prognostic analysis was conducted to evaluate whether the signature could be considered a prognostic factor independent of other variables. A nomogram was constructed in conjunction with traditional clinical variables. The concordance index (C-index) and Decision Curve Analysis (DCA) were used to assess the net clinical benefit of the signature over traditional clinical variables. Seven different softwares were used to compare the differences in immune infiltration between the high- and low-risk groups to explore potential mechanisms of glioma development and prognosis. Hub genes were found using the random forest method, and their expression was based on multiple single-cell datasets. Four molecular subtypes were identified, among which the C1 group had the worst prognosis. Principal Component Analysis (PCA) results and heatmaps indicated that prognosis-related transmembrane protein genes exhibited differential expression in all four groups. Besides, the microenvironment of the four groups exhibited significant heterogeneity. The 6 gene-based signatures could predict the 1-, 2-, and 3-year overall survival (OS) of glioma patients. The signature could be used as an independent prognosis factor of glioma OS and was superior to traditional clinical variables. More immune cells were infiltrated in the high-risk group, suggesting immune escape. According to our signature, many genes were associated with the content of immune cells, which revealed that transmembrane protein-related genes might influence the development and prognosis of glioma by regulating the immune microenvironment. TMEM158 was identified as the most important gene using the random forest method. The single-cell datasets consistently showed that TMEM158 was expressed in multiple malignant cells. The expression of transmembrane protein-related genes is closely related to the immune status and prognosis of glioma patients by regulating tumor progression in various ways. The interaction between transmembrane protein-related genes and immunity during glioma development lays the groundwork for future studies on the molecular mechanism and targeted therapy of glioma.