肝细胞肝癌肿瘤异质性及分子演进机制

The tumor heterogeneity and molecular evolution mechanism of hepatocellular carcinoma

目的探讨肝细胞肝癌(LIHC)的瘤内异质性及肿瘤演进机制。方法从TCGA数据库下载肝细胞肝癌的mRNA表达数据及拷贝数变异数据。使用R软件中NMF包对肝细胞肝癌样本进行聚类,并对聚类结果进行PCA分析,使用GSEABase和ESTIMATE包行免疫微环境和免疫浸润分析,使用limma包筛选差异表达基因。对筛选的基因行网络互作和功能富集分析。使用GISTIC方法分析肝细胞肝癌拷贝数变异。结果肝细胞肝癌惠者可分为两个不同亚组NMF1组和NMF2组,两组在免疫评分、肿瘤纯度、免疫细胞组成等方面均显著不同(P<0.05)。NMF1组与对照组免疫状态相似,均高于NMF2组。GO和KEGG结果显示,肝细胞肝癌始终在细胞分裂、染色体端粒、P53信号通路等发生异常改变;NMF1组为代谢通路、PPAR信号通路改变;NMF2组为NOD样受体信号通路、细胞因子受体相互作用等。拷贝数变异分析结果显示拷贝数改变的基因有2042个,NMF1组有35个,NMF2组有20个。结论肝细胞肝癌急者分为两个亚型,NMF1组患者更适合辅助代谢相关治疗和免疫治疗。

Objective To explore the intratumoral heterogeneity of liver hepatocellular carcinoma(LIHC)and the molecular mechanism of tumor evolution from the molecular level.Methods The mRNA expression data was downloaded from the TCGA database.The NMF package of R software was applied to cluster liver hepatocellular carcinoma samples and PCA analysis followed.GSEABase and ESTIMATE packages were used for immune microenvironment and immune infiltration analysis.The differentially expression genes(DEGs)were identified by limma package.Then the selected genes were conducted with function and pathway analysis and protein-protein network analysis.Results Two subtypes NMF1 and NMF2 were identified from liver hepatocellular carcinoma samples,and the immune score,tumor purity and immune cell components were significantly different between those subtypes(P<0.05).The immune status of NMF1 and control group were similar,and higher than NMF2 group.GO and KEGG analysis showed that the abnormally altered functions and pathways of liver hepatocellular carcinoma were cell division,chromosome telomere and P53 signaling pathway,while metabolic pathway and PPAR signaling pathway in NMF1 and NOD-like receptor signaling pathway,and cytokine-cytokine receptor interaction in NMF2.The results of copy number variation analysis showed 2042 genes and 35genes belong to NMF1 group and 20 genes belong to NMF2 group.Conclusion There are two subtypes in liver hepatocellular carcinoma patients.Patients in the NMF1 group are more suitable to consider adjuvant treatment from metabolism and immunity.