Title:Exploration of Key Genes Combining with Immune Infiltration Level and
Tumor Mutational Burden in Hepatocellular Carcinoma
Volume: 27
Issue: 14
Author(s): Jing Chen, Lu Zhang, Cui-Hua Lu*Chen-Zhou Xu*
Affiliation:
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University,
Nantong, China
- The First Hospital of Jiaxing Affiliated Hospital of Jiaxing University, Jiaxing, China
Keywords:
Hepatocellular carcinoma (HCC), tumor mutational burden (TMB), tumor immune infiltration, tumor immune microenvironment (TIME), prognosis, differentially expressed genes (DEGs).
Abstract:
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.
Conclusion: 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.