Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.