Comprehensive analysis of TMEM9 in human tumors.

Background: TMEM9, a transmembrane protein, has emerged as a significant player in tumor progression, yet its comprehensive role across various cancers remains unclear. This study investigates the expression patterns, genetic alterations, immune associations, and prognostic implications of TMEM9 across multiple cancer types using large-scale bioinformatics approaches.

Methods: TMEM9 expression was analyzed in normal and tumor tissues using data from the TCGA and GTEx databases, with protein expression verified via CPTAC datasets. The prognostic impact of TMEM9 was assessed using overall survival (OS) and disease-free survival (DFS) analyses across various cancers. Genetic alterations, including mutation types and copy number alterations, were explored using the cBioPortal platform. We also examined DNA methylation, RNA modifications, and immune infiltration correlations using bioinformatics tools, including TIMER2 and UALCAN. TMEM9's relationship with tumor mutational burden (TMB) and microsatellite instability (MSI) was analyzed, and gene enrichment analyses were performed using the STRING database and GO/KEGG pathway analyses.

Results: TMEM9 was significantly overexpressed in several cancers, including ACC, BLCA, BRCA, CHOL, COAD, GBM, and others. Elevated TMEM9 expression correlated with worse OS and DFS in ACC, CESC, KICH, UVM, and additional tumor types. Genetic alterations, predominantly amplifications, were frequent in BRCA, LIHC, and UCEC. DNA methylation analysis revealed hypermethylation in tumors like HNSC and KIRC, while RNA modification analyses showed TMEM9 associations with m6A and m1A-related genes. TMEM9 expression was strongly correlated with immune infiltration, particularly cancer-associated fibroblasts in tumors like THYM and HNSC. Positive associations between TMEM9 and TMB/MSI were observed in several cancers, suggesting genomic instability. Enrichment analyses identified TMEM9 involvement in pathways related to the endoplasmic reticulum, Wnt signaling, and protein processing.

Conclusion: TMEM9 plays a crucial role in cancer progression, influencing gene expression, immune modulation, and genomic instability. These findings highlight TMEM9 as a potential prognostic biomarker and therapeutic target across multiple cancer types.