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Identifying potential therapeutic targets in lung adenocarcinoma: a multi-omics approach integrating bulk and
Youpeng Chen1, Enzhong Li2, Zhenglin Chang1
1Department of Clinical Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
Abstract:
Our research aimed to identify new therapeutic targets for Lung adenocarcinoma (LUAD), a major subtype of non-small cell lung cancer known for its low 5-year survival rate of 22%. By employing a comprehensive methodological approach, we analyzed bulk RNA sequencing data from 513 LUAD and 59 non-tumorous tissues, identifying 2,688 differentially expressed genes. Using Mendelian randomization (MR), we identified 74 genes with strong evidence for a causal effect on risk of LUAD. Survival analysis on these genes revealed significant differences in survival rates for 13 of them. Our pathway enrichment analysis highlighted their roles in immune response and cell communication, deepening our understanding. We also utilized single-cell RNA sequencing (scRNA-seq) to uncover cell type-specific gene expression patterns within LUAD, emphasizing the tumor microenvironment's heterogeneity. Pseudotime analysis further assisted in assessing the heterogeneity of tumor cell populations. Additionally, protein-protein interaction (PPI) network analysis was conducted to evaluate the potential druggability of these identified genes. The culmination of our efforts led to the identification of five genes (tier 1) with the most compelling evidence, including SECISBP2L, PRCD, SMAD9, C2orf91, and HSD17B13, and eight genes (tier 2) with convincing evidence for their potential as therapeutic targets.
Insights
Researchers identified novel therapeutic targets for lung adenocarcinoma (LUAD), a deadly cancer. Key genes involved in immune response and cell communication were pinpointed, offering new avenues for LUAD treatment strategies.
Area of Science:
- Oncology
- Genomics
- Bioinformatics
Background:
- Lung adenocarcinoma (LUAD) has a poor 5-year survival rate (22%).
- Identifying novel therapeutic targets is crucial for improving LUAD patient outcomes.
- Understanding LUAD's molecular complexity and tumor microenvironment is essential.
Purpose of the Study:
- To identify and validate novel therapeutic targets for LUAD.
- To investigate the causal genetic factors influencing LUAD risk.
- To explore LUAD heterogeneity and druggable targets.
Main Methods:
- Bulk and single-cell RNA sequencing (scRNA-seq) of LUAD tissues.
- Mendelian randomization (MR) for causal inference of gene effects.
- Survival analysis, pathway enrichment, and protein-protein interaction (PPI) network analysis.
Main Results:
- Identified 2,688 differentially expressed genes in LUAD.
- Discovered 74 genes causally linked to LUAD risk via MR, with 13 impacting survival.
- Highlighted roles in immune response and cell communication; identified 5 tier 1 and 8 tier 2 potential therapeutic targets.
Conclusions:
- The study identified promising therapeutic targets for LUAD, including SECISBP2L, PRCD, SMAD9, C2orf91, and HSD17B13.
- Findings deepen the understanding of LUAD pathogenesis and heterogeneity.
- The identified genes offer potential for developing new LUAD treatment strategies.
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