Department of Hepatobiliary Pancreatic Surgery, Guangzhou First People's Hospital, 510000 Guangzhou, Guangdong, China.
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 510060 Guangzhou, Guangdong, China.
Front Biosci (Landmark Ed). 2024 Jul 2;29(7):243. doi: 10.31083/j.fbl2907243.
The tumour mutation burden (TMB) is a valuable indicator of the accumulation of somatic mutations, and is thought to be associated with the biological behaviour and prognosis of tumours. However, the related genetic mechanism for these association is still unclear. The aim of the present study was to identify the key gene(s) associated with TMB in hepatocellular carcinoma (HCC) and to investigate its biological functions, downstream transcription factors, and mechanism of action.
Patients in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) database were classified according to TMB signature-related genes. Key genes related to the TMB signature and tumour prognosis were identified. Immunohistochemistry and Quantitative Real-Time Polymerase Chain Reaction (qPCR) were then used to assess gene expression in clinical HCC tissues and HCC cells. Cells with altered gene expression were evaluated for the effect on cell proliferation and apoptosis, both and . Three independent databases and cell sequencing data were used to identify the mechanisms involved and the downstream transcription factors. The mechanism was also studied by altering the expression of downstream transcription factors .
The integrated cluster (IC) 2 group, characterized by 99 TMB signature-related genes, showed a significant different TMB score compared to the IC1 group ( < 0.001), as well as more favourable tumour prognosis ( = 0.031). We identified five key prognostic genes that were differentially expressed between IC2 and IC1 and were associated with overall survival. The expression of one of these key prognostic genes, , was negatively correlated with TMB in 18 out of 33 tumour types examined. A high level of was correlated with better overall survival in HCC ( = 0.0009). Overexpression of enhanced apoptosis and , whereas knockdown of attenuated apoptosis. The mechanism by which promotes apoptosis may involve upregulation of the expression of ETS homologous factor () and of death receptor 5 ().
Downregulation of expression was found to correlate with elevated TMB in multiple cancer types. was also found to be a biomarker of HCC prognosis, and to promote the apoptosis of HCC cells through the pathway. These findings provide a new perspective on systemic treatment for advanced HCC with a high TMB.
肿瘤突变负荷（TMB）是体细胞突变积累的一个有价值的指标，被认为与肿瘤的生物学行为和预后相关。然而，这些关联的相关遗传机制尚不清楚。本研究旨在确定与肝细胞癌（HCC）TMB 相关的关键基因，并研究其生物学功能、下游转录因子和作用机制。
根据 TMB 特征相关基因对 TCGA-LIHC 数据库中的患者进行分类。确定与 TMB 特征和肿瘤预后相关的关键基因。然后使用免疫组织化学和定量实时聚合酶链反应（qPCR）评估临床 HCC 组织和 HCC 细胞中的基因表达。改变基因表达的细胞用于评估对细胞增殖和凋亡的影响。使用三个独立的数据库和细胞测序数据来确定所涉及的机制和下游转录因子。通过改变下游转录因子的表达来研究该机制。
整合聚类（IC）2 组，特征为 99 个 TMB 特征相关基因，与 IC1 组相比，TMB 评分有显著差异（<0.001），并且肿瘤预后更好（=0.031）。我们鉴定了 5 个关键预后基因，它们在 IC2 和 IC1 之间表达不同，与总生存期相关。这些关键预后基因中的一个，即，在 33 种检查的肿瘤类型中的 18 种中与 TMB 呈负相关。HCC 中高水平的与更好的总生存期相关（=0.0009）。过表达增强了凋亡和，而则减弱了凋亡。通过上调转录因子（ETS 同源因子（）和死亡受体 5（DR5））来促进凋亡的机制。
下调表达与多种癌症类型中 TMB 的升高相关。还发现是 HCC 预后的生物标志物，并通过途径促进 HCC 细胞的凋亡。这些发现为高 TMB 的晚期 HCC 的系统治疗提供了新的视角。
