There is growing evidence that pseudogenes may serve as prognostic biomarkers in several cancers. The present study was designed to develop and validate an accurate and robust pseudogene pairs-based signature for the prognosis of hepatocellular carcinoma (HCC). RNA-sequencing data from 374 HCC patients with clinical follow-up information were obtained from the Cancer Genome Atlas (TCGA) database and used in this study. Survival-related pseudogene pairs were identified, and a signature model was constructed by Cox regression analysis (univariate and least absolute shrinkage and selection operator). All individuals were classified into high- and low-risk groups based on the optimal cutoff. Subgroups analysis of the novel signature was conducted and validated in an independent cohort. Pearson correlation analyses were carried out between the included pseudogenes and the protein-coding genes based on their expression levels. Enrichment analysis was performed to predict the possible role of the pseudogenes identified in the signature. A 19-pseudogene pair signature, which included 21 pseudogenes, was established. Patients in high-risk group demonstrated an increased the risk of adverse prognosis in the TCGA cohort and the external cohort (all P < 0.001). The novel pseudogene signature was independent of other conventional clinical variables used for survival prediction in HCC patients in the two cohorts revealed by the multivariate Cox regression analysis (all P < 0.001). Subgroup analysis further demonstrated the diagnostic value of the signature across different stages, grades, sexes, and age groups. The C-index of the prognostic signature was 0.761, which was not only higher than that of several previous risk models but was also much higher than that of a single age, sex, grade, and stage risk model. Furthermore, functional analysis revealed that the potential biological mechanisms mediated by these pseudogenes are primarily involved in cytokine receptor activity, T cell receptor signaling, chemokine signaling, NF-κB signaling, PD-L1 expression, and the PD-1 checkpoint pathway in cancer. The novel proposed and validated pseudogene pair-based signature may serve as a valuable independent prognostic predictor for predicting survival of patients with HCC.

中文翻译：

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新型基于假基因对的预后签名的开发和验证，可预测肝细胞癌患者的总体生存率。

越来越多的证据表明，假基因可能在几种癌症中充当预后生物标志物。本研究旨在开发和验证准确，可靠的基于假基因对的签名，用于肝细胞癌（HCC）的预后。从癌症基因组图谱（TCGA）数据库获得了374例具有临床随访信息的HCC患者的RNA测序数据，并将其用于本研究。鉴定与生存相关的假基因对，并通过Cox回归分析（单变量和最小绝对收缩和选择算子）构建特征模型。根据最佳临界值将所有个体分为高风险和低风险组。在一个独立的队列中进行并验证了新特征的亚组分析。基于它们的表达水平，在包括的假基因和蛋白质编码基因之间进行了皮尔逊相关分析。进行富集分析以预测在签名中鉴定的假基因的可能作用。建立了一个19个假基因对签名，其中包括21个假基因。高风险组患者在TCGA队列和外部队列中显示出不良预后的风险增加（所有P <0.001）。新的假基因特征与多变量Cox回归分析揭示的两个队列中HCC患者生存预测所用的其他常规临床变量无关（所有P <0.001）。亚组分析进一步证明了签名在不同阶段，等级，性别和年龄组中的诊断价值。预后标志的C指数为0.761，不仅高于先前的几种风险模型，而且也远高于单一年龄，性别，年级和阶段风险模型的C指数。此外，功能分析表明，由这些假基因介导的潜在生物学机制主要涉及癌症中的细胞因子受体活性，T细胞受体信号传导，趋化因子信号传导，NF-κB信号传导，PD-L1表达和PD-1检查点途径。新的提出并验证的基于假基因对的签名可以作为有价值的独立预后因子，用于预测HCC患者的生存。此外，功能分析表明，由这些假基因介导的潜在生物学机制主要涉及癌症中的细胞因子受体活性，T细胞受体信号传导，趋化因子信号传导，NF-κB信号传导，PD-L1表达和PD-1检查点途径。新的提出并验证的基于假基因对的签名可以作为有价值的独立预后因子，用于预测HCC患者的生存。此外，功能分析表明，由这些假基因介导的潜在生物学机制主要涉及癌症中的细胞因子受体活性，T细胞受体信号传导，趋化因子信号传导，NF-κB信号传导，PD-L1表达和PD-1检查点途径。新颖的提出和验证的基于假基因对的签名可以作为有价值的独立预后因子，用于预测HCC患者的生存。