Construction of a Novel LncRNA Signature Related to Genomic Instability to Predict the Prognosis and Immune Activity of Patients With Hepatocellular Carcinoma.
Construction of a Novel LncRNA Signature Related to Genomic Instability to Predict the Prognosis and Immune Activity of Patients With Hepatocellular Carcinoma.
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DOI：
10.3389/fimmu.2022.856186
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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基因组不稳定性（GI）在包括肝细胞癌在内的各种癌症的发展中起着至关重要的作用。因此，我们使用与基因组不稳定性相关的长非编码RNA来构建HCC患者的预后标志是有意义的。结合癌症基因组图谱数据库中的lncRNA表达谱和体细胞突变谱，我们鉴定了GI相关的lncRNA（GILncRNA），并通过单变量回归分析获得了与癌症相关的GILncRNA。这些lncRNA通过多变量回归分析获得风险系数，用于构建GI相关lncRNA签名（GILncSig）。ROC曲线用于评估签名性能。国际癌症基因组学联盟（ICGC）队列和体外实验用于签名外部验证。采用TIDE、ESTIMATE、pRRophetic和ssGSEA程序比较高风险组和低风险组的免疫治疗效果、肿瘤微环境、半数最大抑制浓度（IC 50）和免疫浸润。使用五种GILncRNA构建GILncSig。通过绘制时间依赖性ROC曲线，证实GILncSig对HCC患者具有良好的预后评估性能。根据GILncSig风险评分将患者分为高风险组和低风险组。低危组预后明显好于高危组。独立预后分析显示GILncSig可独立预测HCC患者的预后。此外，GILncSig与HCC基因组的突变率相关，表明其具有测量基因组不稳定性程度的潜力。在GILncSig中，具有最高风险因子的LUCAT1被进一步验证为体外HCC的风险因子。ESTIMATE分析显示两组间基质评分和ESTIMATE评分存在显著差异。多个免疫检查点在高危组中表达水平较高。ssGSEA结果显示，与高风险组相比，低风险组中肿瘤拮抗免疫细胞的水平更高。最后，GILncSig评分与HCC患者的化疗药物敏感性和免疫治疗疗效相关。我们的研究表明，GILncSig可用于HCC患者的预后评估，并为临床决策和潜在的治疗策略提供新的见解。
Genomic instability (GI) plays a crucial role in the development of various cancers including hepatocellular carcinoma. Hence, it is meaningful for us to use long non-coding RNAs related to genomic instability to construct a prognostic signature for patients with HCC. Combining the lncRNA expression profiles and somatic mutation profiles in The Cancer Genome Atlas database, we identified GI-related lncRNAs (GILncRNAs) and obtained the prognosis-related GILncRNAs through univariate regression analysis. These lncRNAs obtained risk coefficients through multivariate regression analysis for constructing GI-associated lncRNA signature (GILncSig). ROC curves were used to evaluate signature performance. The International Cancer Genomics Consortium (ICGC) cohort, and in vitro experiments were used for signature external validation. Immunotherapy efficacy, tumor microenvironments, the half-maximal inhibitory concentration (IC50), and immune infiltration were compared between the high- and low-risk groups with TIDE, ESTIMATE, pRRophetic, and ssGSEA program. Five GILncRNAs were used to construct a GILncSig. It was confirmed that the GILncSig has good prognostic evaluation performance for patients with HCC by drawing a time-dependent ROC curve. Patients were divided into high- and low-risk groups according to the GILncSig risk score. The prognosis of the low-risk group was significantly better than that of the high-risk group. Independent prognostic analysis showed that the GILncSig could independently predict the prognosis of patients with HCC. In addition, the GILncSig was correlated with the mutation rate of the HCC genome, indicating that it has the potential to measure the degree of genome instability. In GILncSig, LUCAT1 with the highest risk factor was further validated as a risk factor for HCC in vitro. The ESTIMATE analysis showed a significant difference in stromal scores and ESTIMATE scores between the two groups. Multiple immune checkpoints had higher expression levels in the high-risk group. The ssGSEA results showed higher levels of tumor-antagonizing immune cells in the low-risk group compared with the high-risk group. Finally, the GILncSig score was associated with chemotherapeutic drug sensitivity and immunotherapy efficacy of patients with HCC. Our research indicates that GILncSig can be used for prognostic evaluation of patients with HCC and provide new insights for clinical decision-making and potential therapeutic strategies.