Rong Fan, Cheng Bin, Guo Ling, Zeng Shaobo, Xu Xunliang, Meng Zhongji
Department of Infectious Diseases, Institute of Biomedical Research, Regulatory Mechanism and Targeted Therapy for Liver Cancer Shiyan Key Laboratory, Hubei provincial Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
Department of Hepatobiliary Pancreatic Surgery, Wudangshan Branch of Taihe Hospital, Hubei University of Medicine, Shiyan, China.
PLoS One. 2025 Jun 2;20(6):e0325033. doi: 10.1371/journal.pone.0325033. eCollection 2025.
Mitochondrial DNA (mtDNA) is an important genetic material in eukaryotic cells. Mitochondrial DNA maintenance-related gene (mtDNA MRG) variants contribute to mitochondrial dysfunction in cancer progression and are associated with cancer prognosis. However, the mechanism of mtDNA MRGs in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC) remains unclear.
Data for a total of 487 HCC samples were collected from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). The mitochondrial regulatory pathway gene set was downloaded, and 22 mtDNA MRGs were identified by screening. Based on these 22 genes, the HCC samples were grouped by unsupervised clustering based on a machine learning model. Principal component analysis (PCA) was used to construct the mtDNA score model, and the relationships between the mtDNA score and clinicopathological features, tumor mutation burden (TMB), TME cell infiltration and biological processes were analyzed.
The expression of 22 mtDNA MRGs significantly different in HCC samples vs. normal controls. In this study, HCC samples were divided into three molecular subtypes based on the expression of mtDNA MRGs. The three subtypes exhibit different clinical characteristics and immune infiltration profiles, and the cell infiltration profiles corresponded to the immune rejection, immune inflammation, and immune-desert phenotypes, respectively. A total of 740 core genes were obtained from different molecular subtypes, and these genes were divided into three gene subtypes. The mtDNA score model, which can be used to assess tumor immune cell invasion, clinicopathological features, genetic variation, and prognosis, was subsequently constructed. A high mtDNA score was associated with a high mutation burden, high clinical stage and poor prognosis.
mtDNA MRGs play important roles in HCC TMB, prognosis, clinicopathological features and the immune microenvironment. The mtDNA score can be used to evaluate HCC prognosis, TMB and the immune microenvironment, thereby providing guidance for treatment decision making and prognosis prediction in HCC patients.
线粒体DNA（mtDNA）是真核细胞中的重要遗传物质。线粒体DNA维持相关基因（mtDNA MRG）变异在癌症进展中导致线粒体功能障碍，并与癌症预后相关。然而，mtDNA MRGs在肝细胞癌（HCC）肿瘤微环境（TME）中的作用机制仍不清楚。
从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）收集了总共487个HCC样本的数据。下载线粒体调节通路基因集，并通过筛选鉴定出22个mtDNA MRGs。基于这22个基因，根据机器学习模型对HCC样本进行无监督聚类分组。主成分分析（PCA）用于构建mtDNA评分模型，并分析mtDNA评分与临床病理特征、肿瘤突变负荷（TMB）、TME细胞浸润及生物学过程之间的关系。
22个mtDNA MRGs在HCC样本与正常对照中的表达存在显著差异。在本研究中，根据mtDNA MRGs的表达将HCC样本分为三种分子亚型。这三种亚型表现出不同的临床特征和免疫浸润谱，细胞浸润谱分别对应免疫排斥、免疫炎症和免疫沙漠表型。从不同分子亚型中总共获得740个核心基因，这些基因被分为三种基因亚型。随后构建了可用于评估肿瘤免疫细胞浸润、临床病理特征、基因变异和预后的mtDNA评分模型。高mtDNA评分与高突变负荷、高临床分期和不良预后相关。
mtDNA MRGs在HCC的TMB、预后、临床病理特征和免疫微环境中起重要作用。mtDNA评分可用于评估HCC的预后、TMB和免疫微环境，从而为HCC患者的治疗决策和预后预测提供指导。
