目的：运用生物信息学方法筛选年轻肝细胞癌（hepatocellular carcinoma，HCC）患者特有的关键枢纽基因（Hub gene），并探索其生物学和临床意义。方法:从GEO芯片数据集GSE45267获取年轻（确诊HCC时年龄≤40岁）和年老（确诊HCC 时年龄>40岁）组的HCC组织及正常肝组织数据信息，通过GEO2R和Venn图工具筛选两组的HCC组织相对正常肝组织差异表 达基因（differentially expressed gene，DEG），运用STRING和Cytoscape软件构建年轻组特有差异表达基因的蛋白互作网络并筛 选关键Hub基因及显著模块。利用GEPIA数据库对关键基因进行验证，并通过Kaplan–Meier分析相关HCC患者总生存期。最 后应用DAVID对年轻组特有基因及年轻与年老组共有DEGs进行GO富集分析和KEGG通路分析比较。结果：筛选出年轻组特 有117个上调、179个下调DEGs，构建PPI网络选取出10个连接度最高的基因为Hub基因，其中7个Hub基因集中于第一模块。 GEPIA验证与Kaplan–Meier生存分析提示TYMS、CDC6、BUB1、TPX2、OIP5、KIF23等6个表达上调的Hub基因可能与年轻HCC 癌患者的不良预后相关。功能富集分析显示年轻HCC特有DEGs主要参与ATP结合等生物学过程，并主要富集到了细胞周期S 期；年轻与年老组共有DEGs主要参与环氧酶P450、细胞分裂等生物学过程，并主要富集到细胞周期G2/M期。结论:本研究鉴定 出6个在年轻HCC患者肿瘤组织中特有的显著上调且提示预后不良的Hub基因，可能成为年轻HCC患者潜在的治疗和预后预 测靶点。

Objective: To identify the specific Hub genes in young hepatocellular carcinoma (HCC) patients, and to explore their biological and clinical significance by using bioinformatic methods. Methods: The data information of HCC and normal tissues of young (≤40 years old at diagnosis) and old (＞40 years old at diagnosis) HCC patients were obtained from GEO chip data set GSE45267. The differentially expressed genes (DEGs) in HCC tissues as comparing to normal tissues in the two groups were screened by using GEO2R and Venn chart software. The Protein-Protein Interaction (PPI) network of the specific DEGs in young group was constructed by bioinformatics tools STRING and Cytoscape to screen the Hub genes and significant modules. The Hub genes were verified by GEPIA database, and the overall survival time was analyzed by Kaplan-Meier. Finally, Gene Ontology (GO) Enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to analyze the DEGs specific to young group and the common DEGs of the two groups by DAVID. Results: Finally, 117 up-regulated and 179 down-regulated DEGs specific to the young group were screened out, and PPI network screened 10 most connected genes as Hub genes, among which 7 Hub genes were concentrated in the first module. Six up-regulated Hub genes, including TYMS, CDC6, BUB1, TPX2, OIP5 and KIF23, were indicated to associate with the poor prognosis in young HCC patients by GEPIA and Kaplan-Meier analysis. GO function and KEGG pathway analyses showed that the DEGs specific to young HCC patients were mainly involved in biological processes such as ATP binding, and were mainly enriched in S phase of cell cycle; while the common DEGs of two groups were mainly involved in biological processes such as cyclooxygenase P450 and cell division, and were mainly enriched in the G2/M phase of the cell cycle. Conclusion: In this study, 6 up-regulated DEGs specific to young group that suggested poor prognosis were identified, which may be the potential therapeutic and prognostic targets for young patients with HCC.

国家重点基础研究发展（973计划）计划资助项目（No. 2015CB755400）；江苏省苏北人民医院院级扶持技术项目（No. fcjs201748）