Deciphering RNA and protein expression discordance identifies TOP2A as a prognostic biomarker and potential therapeutic target in lung adenocarcinoma

OBJECTIVE: Understanding the discordance between RNA and protein expression can help elucidate underlying disease mechanisms that cannot be fully explained using transcriptomic information alone. Unveiling novel mechanisms of tumorigenesis through multi-omics data using real-world data is central to advancing precision in oncology and tumor prevention. In this study, we investigated the expression discordance between non-tumor and tumor patient samples to elucidate the underlying mechanism of tumorigenesis in lung adenocarcinoma (LUAD). METHODS: We performed a correlation analysis of RNA and protein using normal tissue adjacent to tumor and tumor samples to identify distinct expression profiles to unveil tumorigenesis. Publicly available multi-omics data, including RNA, proteins, phosphoproteins, and acetyl proteins, were obtained from the Clinical Proteomic Tumor Analysis Consortium. Gene expression analysis at the single-cell level was performed using single-cell RNA sequencing data. A transformer model was used for in silico drug screening. RESULTS: Most genes in tumors showed a positive correlation between RNA and protein expression. DNA topoisomerase II alpha (TOP2A) and Cyclin-dependent kinase 1 showed a drastic correlation during tumorigenesis in patient with LUAD. TOP2A gene and protein expression were associated with overall survival in patients with LUAD. Single-cell RNA sequencing revealed that highly correlated genes were clustered as distinct subpopulations. TOP2A expression was associated with TP53 genomic status and miR-26A1 expression, which targets TOP2A gene. In silico screening identified novel drugs that could specifically target TOP2A. CONCLUSIONS: Our findings elucidated the multi-layer expression profiles of LUAD, revealing its tumorigenesis and potential clinical implications and interventions.