Souza Vanessa G P, Benard Katya H, Stewart Greg L, Enfield Katey S S, Lam Wan L
British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.
Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
Cancers (Basel). 2025 Mar 15;17(6):996. doi: 10.3390/cancers17060996.
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.
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.
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.
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，肺腺癌（LUAD）是主要亚型。尽管靶向治疗取得了进展，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（GI）是癌症的一个标志，定义为DNA突变和改变的倾向增加，与癌症的发生、进展及治疗耐药密切相关。新出现的证据表明，长链非编码RNA（lncRNA）——长度超过200个核苷酸、不编码蛋白质但调节基因表达的分子——在癌症生物学中起关键作用，且与GI有关。然而，LUAD中GI与lncRNA表达之间的关系仍知之甚少。
在本研究中，我们分析了癌症基因组图谱（TCGA）数据库中LUAD样本的lncRNA和mRNA转录谱，并根据同源重组缺陷（HRD）评分对其进行分类。HRD评分是基因组不稳定的三种基于DNA的独立测量指标的未加权总和：杂合性缺失、端粒等位基因不平衡和大规模转变。然后，我们进行了差异基因表达分析，以鉴定与高HRD评分样本相比，低HRD评分样本中上调或下调的lncRNA和mRNA。在此之后，我们进行了相关性分析，以评估HRD评分与lncRNA和mRNA表达之间关联的显著性。
我们鉴定出30种差异表达的lncRNA和200种与基因组不稳定相关的mRNA。使用来自测序实验的RNA相互作用组数据库，我们发现了与GI相关的lncRNA（GI-lncRNA）和与GI相关的mRNA（GI-mRNA）之间相互作用的证据。进一步研究表明，一些GI-lncRNA在LUAD和其他疾病中发挥调节和功能作用。我们还发现，GI-lncRNA有作为预后生物标志物的潜力，特别是与HRD分层相结合时。特定GI-lncRNA的表达与LUAD的初始治疗反应和免疫浸润相关。此外，我们鉴定出了可调节GI-lncRNA的现有药物，为解决LUAD中的GI提供了潜在的治疗策略。
我们的研究结果表明，与GI相关的lncRNA可作为LUAD预后和治疗反应的有价值生物标志物。此外，调节这些lncRNA为解决LUAD中的基因组不稳定提供了潜在的治疗途径。
