Table11_Identifying potential therapeutic targets in lung adenocarcinoma: a multi-omics approach integrating bulk and single-cell RNA sequencing with Mendelian randomization.XLSX

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.

本研究旨在为肺腺癌（Lung adenocarcinoma，LUAD）鉴定新型治疗靶点。肺腺癌是非小细胞肺癌（non-small cell lung cancer）的主要亚型，其5年生存率仅为22%。本研究采用全面的研究方法学策略，对513份肺腺癌组织与59份非肿瘤组织的批量RNA测序（bulk RNA sequencing）数据进行分析，共鉴定出2688个差异表达基因（differentially expressed genes）。通过孟德尔随机化（Mendelian randomization，MR）分析，本研究筛选出74个对肺腺癌发病风险具有明确因果效应的基因。对上述基因开展生存分析（Survival analysis）后发现，其中13个基因与患者生存率存在显著关联。通路富集分析（pathway enrichment analysis）结果显示，这些基因主要参与免疫应答（immune response）与细胞通讯（cell communication）过程，进一步深化了对肺腺癌发病机制的认知。本研究还利用单细胞RNA测序（single-cell RNA sequencing，scRNA-seq）技术，解析了肺腺癌组织内细胞类型特异性的基因表达模式，重点阐释了肿瘤微环境（tumor microenvironment）的异质性（heterogeneity）；拟时分析（Pseudotime analysis）则辅助评估了肿瘤细胞群体的异质性。此外，本研究开展了蛋白质相互作用（protein-protein interaction，PPI）网络分析，以评估上述候选基因的潜在成药性（druggability）。最终，本研究筛选出5个一级（tier 1）核心基因，包括SECISBP2L、PRCD、SMAD9、C2orf91及HSD17B13，其支持证据最为充分；另有8个二级（tier 2）佐证基因，均具备成为治疗靶点的潜在价值。