Background/Objectives: Non-small cell lung cancer (NSCLC) is the most common type of cancer, with lung adenocarcinoma (LUAD) as the predominant subtype. Despite advancements in targeted therapies, many NSCLC patients still experience poor outcomes due to treatment resistance and disease progression. Genomic instability (GI), a hallmark of cancer, defined as the increased tendency of DNA mutations and alterations, is closely linked to cancer initiation, progression, and resistance to therapy. Emerging evidence suggests that long non-coding RNAs (lncRNAs)—molecules longer than 200 nucleotides that do not encode proteins but regulate gene expression—play critical roles in cancer biology and are associated with GI. However, the relationship between GI and lncRNA expression in LUAD remains poorly understood. Methods: In this study, we analyzed the transcript profiles of lncRNAs and mRNAs from LUAD samples in The Cancer Genome Atlas (TCGA) database and classified them based on their Homologous Recombination Deficiency (HRD) score. The HRD score is an unweighted sum of three independent DNA-based measures of genomic instability: loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions. We then performed a differential gene expression analysis to identify lncRNAs and mRNAs that were either upregulated or downregulated in samples with high HRD scores compared to those with low HRD scores. Following this, we conducted a correlation analysis to assess the significance of the association between HRD scores and the expression of both lncRNAs and mRNAs. Results: We identified 30 differentially expressed lncRNAs and 200 mRNAs associated with genomic instability. Using an RNA interactome database from sequencing experiments, we found evidence of interactions between GI-associated lncRNAs (GI-lncRNAs) and GI-associated mRNAs (GI-mRNAs). Further investigation showed that some GI-lncRNAs play regulatory and functional roles in LUAD and other diseases. We also found that GI-lncRNAs have potential as prognostic biomarkers, particularly when integrated with HRD stratification. The expression of specific GI-lncRNAs was associated with primary therapy response and immune infiltration in LUAD. Additionally, we identified existing drugs that could modulate GI-lncRNAs, offering potential therapeutic strategies to address GI in LUAD. Conclusions: Our findings suggest that GI-associated lncRNAs could serve as valuable biomarkers for LUAD prognosis and therapeutic response. Furthermore, modulating these lncRNAs presents potential treatment avenues to address genomic instability in LUAD.
背景/目的：非小细胞肺癌（NSCLC）是最常见的癌症类型，其中肺腺癌（LUAD）为主要亚型。尽管靶向治疗取得进展，但许多NSCLC患者仍因治疗耐药和疾病进展而预后不良。基因组不稳定性（GI）作为癌症的标志性特征，表现为DNA突变和改变倾向的增加，与癌症的发生、进展及治疗耐药密切相关。新近证据表明，长链非编码RNA（lncRNA）——即长度超过200个核苷酸、不编码蛋白质但调控基因表达的分子——在癌症生物学中发挥关键作用，并与GI相关。然而，GI与LUAD中lncRNA表达的关系尚不明确。方法：本研究通过分析癌症基因组图谱（TCGA）数据库中LUAD样本的lncRNA和mRNA转录谱，依据同源重组缺陷（HRD）评分对其进行分类。HRD评分是三种基于DNA的基因组不稳定性独立指标（杂合性缺失、端粒等位基因失衡和大规模转换）的非加权总和。通过差异基因表达分析，我们筛选出高HRD评分样本相较于低HRD评分样本中表达上调和下调的lncRNA与mRNA。随后进行相关性分析，评估HRD评分与lncRNA及mRNA表达关联的显著性。结果：我们鉴定出30个差异表达的lncRNA和200个与基因组不稳定性相关的mRNA。基于测序实验构建的RNA互作组数据库，我们发现GI相关lncRNA（GI-lncRNA）与GI相关mRNA（GI-mRNA）存在相互作用证据。进一步研究表明，部分GI-lncRNA在LUAD及其他疾病中发挥调控功能。GI-lncRNA具有作为预后生物标志物的潜力，尤其在与HRD分层结合时效果显著。特定GI-lncRNA的表达与LUAD的初始治疗反应及免疫浸润相关。此外，我们发现了可调控GI-lncRNA的现有药物，为干预LUAD的基因组不稳定性提供了潜在治疗策略。结论：本研究表明GI相关lncRNA可作为LUAD预后和治疗反应的重要生物标志物，调控这些lncRNA为干预LUAD的基因组不稳定性提供了潜在治疗途径。
肿瘤(癌症)患者之家