多组学整合揭示染色质相关lncRNA在肺腺癌中的预后模型：连接GWAS、转录组和临床结果

Medicine in Omics Pub Date : 2025-06-26 DOI:10.1016/j.meomic.2025.100045

Xiao Zhu , Zhuolong Xiong

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引用次数: 0

摘要

背景：肺腺癌（LUAD）的特点是总生存率低。本研究旨在探讨长链非编码rna （lncRNAs）与LUAD中染色质组蛋白甲基化/去甲基化修饰因子之间的关系。方法对来自癌症基因组图谱（TCGA）、分子特征数据库（MSigDB）和IEU开放全基因组关联研究（GWAS）数据库的数据进行分析。基于32个与组蛋白修饰相关的lncrna，建立了LUAD的预后风险模型。评估lncrna与肺癌高危人群的关系，并通过GO/KEGG分析探讨染色质组蛋白修饰相关lncrna与生物学过程/途径之间的联系。采用孟德尔随机化方法，包括逆方差加权（IVW）和贝叶斯加权孟德尔随机化（BWMR）来验证GO/KEGG结果。采用MR-Egger截距检验、Cochran’s Q检验和留一分析评价孟德尔随机化分析的敏感性。采用肿瘤突变负荷（Tumor mutation burden， TMB）分析，评价高TMB高危患者的预后影响。结果鉴定的lncrna，包括AC025741.1和NHS-AS1，与高危人群有很强的相关性。GO/KEGG分析显示，染色质组蛋白修饰相关lncrna与微管运动和细胞色素酶P450之间存在显著相关性。肾素-血管紧张素药物的反应是肺癌的保护因素，而糖皮质激素的反应是肺癌的危险因素。免疫标记MDSC、CAF和Exclusion与风险评分呈正相关，CAF和MDSC的联合作用在LUAD的发生和进展中起关键作用。结论本研究不仅建立了一个有前景的LUAD预后风险模型，对LUAD免疫治疗具有潜在的指导意义，而且确定了lncrna作为LUAD免疫治疗的免疫标记物。此外，我们验证了染色质组蛋白甲基化相关途径与肺癌之间的因果关系，从遗传学角度加强了我们的理解，并为LUAD治疗的靶向干预开辟了道路。

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Multi-omics integration reveals chromatin-associated lncRNA prognostic model in lung adenocarcinoma: Bridging GWAS, transcriptome and clinical outcomes

Background

Lung adenocarcinoma (LUAD) is characterized by low overall survival rates. This research aims to explore the association between long non-coding RNAs (lncRNAs) and chromatin histone methylation/demethylation modifiers in LUAD.

Methods

Datasets from The Cancer Genome Atlas (TCGA), Molecular Signatures Database (MSigDB), and IEU Open genome-wide association studies (GWAS) database were analyzed. A prognostic risk model for LUAD was developed based on 32 lncRNAs linked to histone modification. The relationship between lncRNAs and the high-risk group of lung cancer was evaluated, and GO/KEGG analysis was conducted to investigate the connection between chromatin histone modification-related lncRNAs and biological processes/pathways. Mendelian Randomization methods, including Inverse Variance Weighted (IVW) and Bayesian Weighted Mendelian Randomization (BWMR), were employed to validate the GO/KEGG results. MR-Egger intercept test, Cochran’s Q test, and leave-one-out Analysis were utilized to assess the sensitivity of Mendelian Randomization analysis. Tumor mutation burden (TMB) analysis was performed to evaluate the prognostic impact of high-risk patients with high TMB.

Results

Identified lncRNAs, including AC025741.1 and NHS-AS1, demonstrated strong associations with the high-risk group. GO/KEGG analysis revealed significant correlations between chromatin histone modification-related lncRNAs and microtubule-based movement and cytochrome enzyme P450. Response to the renin-angiotensin agents is a protective factor for lung cancer, while response to glucocorticoids is a risk factor for lung cancer. Immunomarkers MDSC, CAF, and Exclusion showed positive correlations with the risk score, and the combined effects of CAF and MDSC were found to play a pivotal role in LUAD development and progression.

Conclusion

Our study not only establishes a promising LUAD prognostic risk model with potential implications for immunotherapy but also identifies lncRNAs as immune markers for LUAD immunotherapy. Additionally, we validate the causal relationship between chromatin histone methylation-related pathways and lung cancer, bolstering our understanding from a genetic perspective and opening avenues for targeted interventions in LUAD treatment.

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Medicine in Omics

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