肿瘤细胞治疗研究
英文原题：Integrating plasma-derived circulating proteins with multi-omics approaches to identify potential therapeutic targets for esophageal adenocarcinoma.
背景：食管腺癌（EAC）是一种复杂疾病，常以巴雷特食管为先兆。
背景：食管腺癌（EAC）是一种复杂疾病，常以巴雷特食管为先兆。目的：本研究旨在识别潜在药物靶点，为早期预防和治疗提供支持。方法：我们整合了35 559名个体的顺式蛋白定量性状位点（cis-pQTLs）和全基因组关联研究（GWAS）数据，采用孟德尔随机化推断因果关系，并应用FDR校正。为评估组织相关性，我们在三个GTEx v8食管组织中检查了来源cis-pQTL工具，随后对CD55和NDST1进行了组织信息指导的单变异Wald分析。采用基因本体（GO）和KEGG通路分析，以及蛋白-蛋白相互作用（PPI）网络分析，探索生物学功能和相互作用。通过GEO数据库的差异表达分析识别重叠基因。使用XGBoost和Lasso回归筛选关键特征基因，并在训练集和验证集中通过ROC曲线AUC评估诊断性能。免疫浸润分析探索肿瘤微环境，分子对接评估药物潜力。结果：我们识别出28种与EAC存在因果关联的血浆蛋白。KEGG分析显示富集于氧化应激和炎症相关通路。转录组验证确认了三个重叠基因。经Lasso和XGBoost筛选后，CD55和NDST1成为具有强诊断准确性的关键标志物。大多数显著的食管SNP-组织关联与相应的血浆pQTL效应方向一致，CD55和NDST1的组织特异性Wald估计与基于血浆的主要发现一致。免疫浸润分析显示EAC中免疫细胞组成发生显著变化，尤其是NK 细胞、浆细胞和肥大细胞。药物预测与分子对接支持这些靶点的可成药性。结论：CD55和NDST1是EAC有前景的治疗候选靶点。基于这些遗传学发现的药物可提高临床试验成功率并降低成本。
Background : Esophageal adenocarcinoma (EAC) is a complex disease often preceded by Barrett's esophagus. Objective : This study aimed to identify potential drug targets and support early prevention and treatment. Method : We integrated cis -protein quantitative trait loci ( cis -pQTLs) and genome-wide association study (GWAS) data from 35 559 individuals using Mendelian randomization to infer causal relationships, with FDR correction applied. To assess tissue relevance, the source cis -pQTL instruments were examined across three GTEx v8 esophageal tissues, followed by tissue-informed single-variant Wald analyses of CD55 and NDST1. Gene ontology (GO) and KEGG pathway analyses, along with protein-protein interaction (PPI) network analysis, were used to explore biological functions and interactions. Overlapping genes were identified through differential expression analysis using the GEO database. Key feature genes were screened using XGBoost and Lasso regression, and diagnostic performance was evaluated by ROC curve AUC in both training and validation sets. Immune infiltration analysis explored the tumor microenvironment, and molecular docking assessed drug potential. Results : We identified 28 plasma proteins causally linked to EAC. KEGG analysis revealed enrichment in oxidative stress and inflammation-related pathways. Transcriptomic validation confirmed three overlapping genes. CD55 and NDST1 emerged as key markers with strong diagnostic accuracy after Lasso and XGBoost screening. Most significant esophageal SNP-tissue associations were directionally concordant with the corresponding plasma pQTL effects, and the tissue-specific Wald estimates for CD55 and NDST1 were consistent with the primary plasma-based findings. Immune infiltration analysis showed significant changes in immune cell composition in EAC, particularly natural killer cells, plasma cells, and mast cells. Drug prediction and docking supported the druggability of these targets. Conclusion : CD55 and NDST1 are promising therapeutic candidates for EAC. Drugs based on these genetic findings could improve clinical trial success rates and reduce costs.
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