背景:由于其异质性和攻击行为,肝细胞癌(HCC)是一种致命的恶性肿瘤。最近,据报道,体细胞突变和肿瘤细胞与周围肿瘤免疫微环境(TIME)的相互作用参与HCC的发生并预测HCC的进展。在这项研究中,我们的目的是研究肝癌中肿瘤突变负荷(TMB)和时间之间的关联。此外,我们试图鉴定与HCC预后和进展相关的差异表达基因(DEGs).
方法:表达式,临床,和突变数据从癌症基因组图谱(TCGA)数据库下载。评估HCC样品的免疫浸润水平和TMB水平,并根据免疫浸润评分将样品分为免疫簇(ICR)-1和2组,根据TMB评分将样品分为高TMB和低TMB组。此后,进行差异基因表达分析以鉴定ICR1/2和高/低TMB组中的DEGs,并选择了相交的DEG。此后,对89个显著DEG进行Cox回归分析,其中19例与预后相关。然后将这19个DEGs用于基于其表达水平和回归系数构建预后模型。此后,我们分析了突变型和野生型TP53HCC样品中的DEGs,并鉴定了突变型TP53样品中BCL10和TRAF3的高表达.通过实时定量逆转录PCR和免疫组织化学检测BCL10和TRAF3的表达,以及它们的临床相关性,生物学功能,和免疫浸润水平通过卡方分析进行分析,基因集富集分析(GSEA),和“ssGSEA”,分别。
结果:我们的研究结果表明,免疫浸润水平与TMB相关,并且它们协同预测HCC患者的不良预后。富含免疫相关途径的DEGs可以作为HCC免疫治疗反应的指标。在这些DEG中,BCL10和TRAF3在肝癌组织中高表达,特别是在突变TP53组中,它们共同表现出免疫功能,从而影响HCC的进展和预后。
结论:在这项研究中,我们确定BCL10和TRAF3是HCC患者的潜在预后指标.此外,我们发现BCL10和TRAF3影响HCC患者的TMB和TIME,可用于开发基于免疫的疗法以改善HCC患者的长期生存率.
BACKGROUND: Hepatocellular carcinoma (HCC) is a lethal malignancy due to its heterogeneity and aggressive behavior. Recently, somatic mutations and tumor cell interactions with the surrounding tumor immune microenvironment (TIME) have been reported to participate in HCC carcinogenesis and predict HCC progression. In this study, we aimed to investigate the association between tumor mutational burden (TMB) and TIME in HCC. Additionally, we sought to identify differentially expressed genes (DEGs) associated with HCC prognosis and progression.
METHODS: The expression, clinical, and mutational data were downloaded from the cancer genome atlas (TCGA) database. The immune infiltration levels and TMB levels of the HCC samples were estimated and the samples were divided into immune cluster (ICR)-1 and 2 based on immune infiltration score and high and low TMB groups based on TMB score. Thereafter, differential gene expression analysis was conducted to identify the DEGs in the ICR1/2 and high/low TMB groups, and the intersecting DEGs were selected. Thereafter, Cox regression analysis was performed on 89 significant DEGs, among which 19 were associated with prognosis. These 19 DEGs were then used to construct a prognostic model based on their expression levels and regression coefficients. Thereafter, we analyzed the DEGs in mutant and wildtype TP53 HCC samples and identified high BCL10 and TRAF3 expression in the mutant TP53 samples. BCL10 and TRAF3 expression was detected by real-time quantitative reverse transcription PCR and immunohistochemistry, and their clinical correlation, biological function, and immune infiltration levels were analyzed by chi-square analyses, Gene Set Enrichment Analysis (GSEA), and \"ssGSEA\", respectively.
RESULTS: The results of our study revealed that immune infiltration level was correlated with TMB and that they synergistically predicted poor prognosis of HCC patients. DEGs enriched in immune-related pathways could serve as indicators of immunotherapy response in HCC. Among these DEGs, BCL10 and TRAF3 were highly expressed in HCC tissues, especially in the mutant TP53 group, and they co-operatively exhibited immunological function, thereby affecting HCC progression and prognosis.
CONCLUSIONS: In this study, we identified BCL10 and TRAF3 as potential prognostic indicators in HCC patients. Additionally, we found that BCL10 and TRAF3 influence TMB and TIME in HCC patients and can be used for the development of immune-based therapies for improving the long-term survival of HCC patients.