Huo Junyu, Fan Xinyi, Qi Bingxin, Sun Peng
Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Allergy, The Affiliated Hospital of Qingdao University, Qingdao, China.
Front Genet. 2022 Jan 20;13:771819. doi: 10.3389/fgene.2022.771819. eCollection 2022.
DNA damage repair (DDR) is an important mechanism for the occurrence and development of hepatocellular carcinoma (HCC), but its impact on prognosis has not been fully understood. A total of 904 HCC patients were included in our study, TCGA ( = 370) and GSE14520 ( = 239) were merged into a large-sample training cohort ( = 609). The training cohort was clustered into C1 and C2 based on prognostic DDR-related genes, the differentially expressed genes (DEGs) between C1 and C2 were identified by the Wilcoxon signed-rank test referred to criteria (|log2FC|≥1 and FDR< 0.05). The univariate Cox analysis was used to screen the prognostic-related DEGs, and Lasso penalized Cox regression analysis was used to construct the risk score. The patients were clarified into high- and low-risk groups based on the median risk score. ICGC ( = 231) and GSE116174 ( = 64) cohorts were used for external validation of the risk score's prognostic value. The Kaplan-Meier survival analysis showed that the high-risk group had a significantly reduced overall survival (OS) compared to the low-risk group in the three independent cohorts, and the time-dependent ROC curve showed that the five-gene (STMN1, PON1, PLOD2, MARCKSL1, and SPP1) risk score with a high accuracy in predicting OS. The patients with AFP >300 ng/ml, tumor poor differentiation (grade 3-4), micro and macro vascular tumor invasion, advanced stage (AJCC III-IV, BCLC stage B-C, and CLIP score >2) exhibited a higher risk score. Subgroup survival analysis found that the risk score was applicable to patients with different clinical characteristics. GO and KEGG functional enrichment analysis revealed that cell cycle, p53 signaling, TNF signaling-related pathways were upregulated in the high-risk group. The higher infiltration level of activated CD4 T cell, CD56 bright natural killer cell, plasmacytoid dendritic cell, and type 2 T helper cells were found to lead an unfavorable impact on the OS of HCC patients, and these four kinds of immune cells exhibited a higher infiltration level in the high-risk group. The five-gene risk score proposed in the research may provide new insights into the individualized evaluation of HCC prognosis.
DNA损伤修复（DDR）是肝细胞癌（HCC）发生发展的重要机制，但其对预后的影响尚未完全明确。本研究共纳入904例HCC患者，将TCGA队列（n = 370）和GSE14520队列（n = 239）合并为一个大样本训练队列（n = 609）。基于预后相关的DDR基因将训练队列分为C1和C2两组，采用Wilcoxon符号秩检验（标准为|log2FC|≥1且FDR<0.05）确定C1和C2之间的差异表达基因（DEG）。采用单因素Cox分析筛选与预后相关的DEG，并使用Lasso惩罚Cox回归分析构建风险评分。根据中位风险评分将患者分为高风险组和低风险组。使用ICGC队列（n = 231）和GSE116174队列（n = 64）对风险评分的预后价值进行外部验证。Kaplan-Meier生存分析显示，在三个独立队列中，高风险组的总生存期（OS）明显低于低风险组，且时间依赖性ROC曲线显示，五基因（STMN1、PON1、PLOD2、MARCKSL1和SPP1）风险评分在预测OS方面具有较高的准确性。甲胎蛋白（AFP）>300 ng/ml、肿瘤低分化（3-4级）、微血管和大血管侵犯、晚期（美国癌症联合委员会III-IV期、巴塞罗那临床肝癌分期B-C期和意大利肝癌协作组评分>2）的患者风险评分较高。亚组生存分析发现，风险评分适用于不同临床特征的患者。基因本体（GO）和京都基因与基因组百科全书（KEGG）功能富集分析显示，高风险组中细胞周期、p53信号传导、肿瘤坏死因子（TNF）信号传导相关通路上调。研究发现，活化的CD4 T细胞、CD56 bright自然杀伤细胞、浆细胞样树突状细胞和2型辅助性T细胞的浸润水平较高对HCC患者的OS产生不利影响，且这四种免疫细胞在高风险组中的浸润水平较高。本研究提出的五基因风险评分可能为HCC预后的个体化评估提供新的见解。
