鉴定和描述一个 25-lncRNA 预后标志物用于预测肝细胞癌早期复发。

BACKGROUND: Early recurrence is the major cause of poor prognosis in hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) are deeply involved in HCC prognosis. In this study, we aimed to establish a prognostic lncRNA signature for HCC early recurrence. METHODS: The lncRNA expression profile and corresponding clinical data were retrieved from total 299 HCC patients in TCGA database. LncRNA candidates correlated to early recurrence were selected by differentially expressed gene (DEG), univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. A 25-lncRNA prognostic signature was constructed according to receiver operating characteristic curve (ROC). Kaplan-Meier and multivariate Cox regression analyses were used to evaluate the performance of this signature. ROC and nomogram were used to evaluate the integrated models based on this signature with other independent clinical risk factors. Gene set enrichment analysis (GSEA) was used to reveal enriched gene sets in the high-risk group. Tumor infiltrating lymphocytes (TILs) levels were analyzed with single sample Gene Set Enrichment Analysis (ssGSEA). Immune therapy response prediction was performed with TIDE and SubMap. Chemotherapeutic response prediction was conducted by using Genomics of Drug Sensitivity in Cancer (GDSC) pharmacogenomics database. RESULTS: Compared to low-risk group, patients in high-risk group showed reduced disease-free survival (DFS) in the training (p < 0.0001) and validation cohort (p = 0.0132). The 25-lncRNA signature, AFP, TNM and vascular invasion could serve as independent risk factors for HCC early recurrence. Among them, the 25-lncRNA signature had the best predictive performance, and combination of those four risk factors further improves the prognostic potential. Moreover, GSEA showed significant enrichment of "E2F TARGETS", "G2M CHECKPOINT", "MYC TARGETS V1" and "DNA REPAIR" pathways in the high-risk group. In addition, increased TILs were observed in the low-risk group compared to the high-risk group. The 25-lncRNA signature negatively associates with the levels of some types of antitumor immune cells. Immunotherapies and chemotherapies prediction revealed differential responses to PD-1 inhibitor and several chemotherapeutic drugs in the low- and high-risk group. CONCLUSIONS: Our study proposed a 25-lncRNA prognostic signature for predicting HCC early recurrence, which may guide postoperative treatment and recurrence surveillance in HCC patients.

背景：早期复发是肝细胞癌（HCC）预后不良的主要原因。长链非编码 RNA（lncRNA）在 HCC 预后中起着重要作用。本研究旨在建立 HCC 早期复发的预后 lncRNA 特征。

方法：从 TCGA 数据库中检索了 299 例 HCC 患者的 lncRNA 表达谱和相应的临床数据。通过差异表达基因（DEG）、单因素 Cox 回归和最小绝对值收缩和选择算子（LASSO）回归分析，选择与早期复发相关的 lncRNA 候选物。根据受试者工作特征曲线（ROC）构建 25-lncRNA 预后特征。Kaplan-Meier 和多因素 Cox 回归分析用于评估该特征的性能。ROC 和列线图用于评估基于该特征与其他独立临床危险因素的综合模型。基因集富集分析（GSEA）用于揭示高危组中富集的基因集。通过单样本基因集富集分析（ssGSEA）分析肿瘤浸润淋巴细胞（TIL）水平。使用 TIDE 和 SubMap 进行免疫治疗反应预测。使用癌症药物敏感性基因组学（GDSC）药物基因组学数据库进行化疗反应预测。

结果：与低危组相比，高危组患者在训练（p<0.0001）和验证队列（p=0.0132）中的无病生存（DFS）降低。25-lncRNA 特征、AFP、TNM 和血管侵犯可作为 HCC 早期复发的独立危险因素。其中，25-lncRNA 特征具有最佳的预测性能，四种危险因素的联合进一步提高了预测潜能。此外，GSEA 显示高危组中“E2F TARGETS”、“G2M CHECKPOINT”、“MYC TARGETS V1”和“DNA REPAIR”途径显著富集。此外，与高危组相比，低危组中观察到 TILs 增加。25-lncRNA 特征与某些类型的抗肿瘤免疫细胞的水平呈负相关。免疫治疗和化疗预测显示，在低危组和高危组中，PD-1 抑制剂和几种化疗药物的反应存在差异。

结论：本研究提出了一种用于预测 HCC 早期复发的 25-lncRNA 预后特征，可为 HCC 患者的术后治疗和复发监测提供指导。