Integrated Pan-Cancer Multi-Omics Analysis Reveals TMEM45A Associated with DNA Hypomethylation, Immune Exclusion, and Drug Response

<title>Abstract</title> <p> <bold>Background</bold> : Transmembrane Protein 45A (TMEM45A) has been implicated in hypoxia tolerance and chemoresistance in several cancers; however, its molecular landscape, epigenetic regulation, and influence on the tumor immune microenvironment (TME) have not been systematically characterized across human malignancies. <bold>Methods</bold> : This study performed an integrated pan-cancer multi-omics analysis across 33 malignancies using transcriptomic, proteomic, epigenomic, pharmacogenomic, and single-cell datasets from TCGA, GTEx, and public resources. Transcriptomic expression, clinicopathology, protein abundance, genomic alterations, DNA methylation, immune infiltration, drug sensitivity, and functional networks were systematically evaluated. Prognostic significance was determined via univariate Cox regression and Kaplan–Meier survival analyses. <bold>Results</bold> : TMEM45A was significantly overexpressed across multiple solid tumors (including BRCA, GBM, HNSC, KIRC, LUSC), where elevated expression correlated with advanced pathological stage and poorer overall (OS) and disease-free survival (DFS). Upregulation was driven by promoter and probe-specific (cg07907506) DNA hypomethylation. Low-frequency copy-number amplifications (up to 8% in LUSC) and recurrent DUF716 domain mutations (V236I) showed limited prognostic value. TMEM45A expression inversely correlated with CD8⁺ T-cell infiltration, but positively associated with cancer-associated fibroblasts (CAFs), M2 macrophages, stromal/immune scores, and immune checkpoints (PDCD1, CTLA4, HAVCR2), indicating an immune-excluded phenotype. Pharmacogenomic analysis revealed consistent inverse sensitivity to docetaxel and a top positive correlation with vorinostat across GDSC and CTRP datasets. <bold>Conclusion</bold> : Integrated network analysis identified TMEM189 as associated with TMEM45A based on convergent protein interaction and transcriptional co-expression analyses. Collectively, these findings establish a comprehensive pan-cancer framework for understanding TMEM45A biology and connect the TMEM45A–TMEM189 network as a molecular axis for future mechanistic and translational investigation. </p>