Fang Xueying, Huang Enmin, Xie Xiaopeng, Yang Kai, Wang Shuqian, Huang Xiaoqing, Song Mei
Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Supported by National Key Clinical Discipline, Department of Gastroenterological Surgery and Hernia Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Front Genet. 2022 Nov 3;13:951311. doi: 10.3389/fgene.2022.951311. eCollection 2022.
Cellular senescence has recently been considered a new cancer hallmark. However, the factors regulating cellular senescence have not been well characterized. The aim of this study is to identify long non-coding RNAs (lncRNAs) associated with senescence and prognosis in patients with lung adenocarcinoma (LUAD). Using RNA sequence data from the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) and senescence genes from the CellAge database, a subset of senescence-related lncRNAs was first identified. Then, using univariate and multivariate Cox regression analyses, a senescence lncRNA signature (LUADSenLncSig) associated with LUAD prognosis was developed. Based on the median LUADSenLncSig risk score, LUAD patients were divided into high-risk and low-risk groups. Kaplan-Meier analysis was used to compare the overall survival (OS) in the high- and low-risk score subgroups. Differences in Gene Set Enrichment Analysis (GSEA), immune infiltration, tumor mutation burden (TMB), tumor immune dysfunction and exclusion (TIDE) module score, chemotherapy, and targeted therapy selection were also compared between the high-risk and low-risk groups. A prognostic risk model was obtained consisting of the following nine senescence-related lncRNAs: LINC01116, AC005838.2, SH3PXD2A-AS1, VIMS-AS1, SH3BP5-AS1, AC092279.1, AC026355.1, AC027020.2, and LINC00996. The LUADSenLncSig high-risk group was associated with poor OS (hazard ratio = 1.17, 95% confidence interval = 1.102-1.242; < 0.001). The accuracy of the model was further supported based on receiver operating characteristic (ROC), principal component analysis (PCA), and internal validation cohorts. In addition, a nomogram was developed consisting of LUADSenLncSig for LUAD prognosis, which is consistent with the actual probability of OS. Furthermore, immune infiltration analysis showed the low-risk group had a stronger anti-tumor immune response in the tumor microenvironment. Notably, the levels of immune checkpoint genes such as CTLA-4, PDCD-1, and CD274, and the TIDE scores were significantly higher in the low-risk subgroups than in high-risk subgroups ( < 0.001). This finding indicates the LUADSenLncSig can potentially predict immunotherapy efficacy. In this study, a lncRNA signature, LUADSenLncSig, that has dual functions of senescence phenotype identification and prognostic prediction as well as the potential to predict the LUAD response to immunotherapy was developed.
细胞衰老最近被认为是一种新的癌症标志。然而，调节细胞衰老的因素尚未得到充分表征。本研究的目的是鉴定与肺腺癌（LUAD）患者衰老和预后相关的长链非编码RNA（lncRNA）。利用来自癌症基因组图谱肺腺癌（TCGA-LUAD）的RNA序列数据和来自CellAge数据库的衰老基因，首先鉴定了一组与衰老相关的lncRNA。然后，使用单变量和多变量Cox回归分析，开发了一种与LUAD预后相关的衰老lncRNA特征（LUADSenLncSig）。根据LUADSenLncSig风险评分中位数，将LUAD患者分为高风险和低风险组。采用Kaplan-Meier分析比较高风险和低风险评分亚组的总生存期（OS）。还比较了高风险组和低风险组之间基因集富集分析（GSEA）、免疫浸润、肿瘤突变负担（TMB）、肿瘤免疫功能障碍和排除（TIDE）模块评分、化疗和靶向治疗选择的差异。获得了一个由以下9个与衰老相关的lncRNA组成的预后风险模型：LINC01116、AC005838.2、SH3PXD2A-AS1、VIMS-AS1、SH3BP5-AS1、AC092279.1、AC026355.1、AC027020.2和LINC00996。LUADSenLncSig高风险组与较差的OS相关（风险比=1.17，95%置信区间=1.102-1.242；P<0.001）。基于受试者工作特征（ROC）、主成分分析（PCA）和内部验证队列，进一步支持了该模型的准确性。此外，开发了一个由LUADSenLncSig组成的用于LUAD预后的列线图，其与OS的实际概率一致。此外，免疫浸润分析表明，低风险组在肿瘤微环境中具有更强的抗肿瘤免疫反应。值得注意的是，低风险亚组中免疫检查点基因如CTLA-4、PDCD-1和CD274的水平以及TIDE评分显著高于高风险亚组（P<0.001）。这一发现表明LUADSenLncSig可能预测免疫治疗疗效。在本研究中，开发了一种lncRNA特征LUADSenLncSig，它具有衰老表型鉴定和预后预测的双重功能，以及预测LUAD对免疫治疗反应的潜力。
