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Comprehensive analysis of genomic and immunological profiles in Chinese and Western hepatocellular carcinoma populations.

ABSTRACT: In this study, we explored the genomic and immune cell infiltration profiles among four distinct Hepatocellular carcinoma (HCC) types. This study included 100 patients (all tumors and adjacent liver tissues received WES sequencing) with HCC from the West China Hospital (WCH) and patients were divided into WCH-HBV-HCC group and WCH-NonHBV-HCC group. Additionally, this study included 106 HBV-related HCC (TCGA-HBV-HCC) and 69 alcoholic HCC (TCGA-Alcol-HCC) patients from the TCGA. We analyzed the high-frequency gene mutation, copy number variation (CNV), mutation spectrum, signatures and immune cell infiltration of these four groups. This study showed significant differences in gene mutation and CNV level among four HCC groups. Compared to genomic level, there is no significant difference between TCGA-HBV-HCC and TCGA-Alcol-HCC groups in fractions of tumor-infiltrating immune cells. According to the status of immune cell infiltration, patients were classified into immune-HIGH, immune-MIX and immune-LOW group, respectively. In the WCH-HBV-HCC and TCGA-HBV-HCC groups, more patients in the Immune-LOW group had TP53 mutation. Except for TP53, neither the other gene mutation nor tumor mutation burden was found to be associated with immune cell infiltration in the WCH-HBV-HCC, TCGA-HBV-HCC and TCGA-Alcol-HCC groups. In the CNV level, we found that samples with low immune infiltrate had higher number of deleted or amplified genes in the TCGA-HBV-HCC and TCGA-Alcol-HCC groups. We found comprehensive genomic heterogeneity among four HCC groups. The total gene CNV level, not the mutational burden of HCC, is associated with immune cell infiltration in HCC. TP53 mutation may injury the immune response of the HBV-related HCC.

SUBMITTER: Li W

PROVIDER: S-EPMC8109067 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHepatocellular carcinoma is the second most deadly cancer with late presentation and limited treatment options, highlighting an urgent need to better understand HCC to facilitate the identification of early-stage biomarkers and uncover therapeutic targets for the development of novel therapies for HCC.MethodsDeep transcriptome sequencing of tumor and paired non-tumor liver tissues was performed to comprehensively evaluate the profiles of both the host and HBV transcripts in HCC patients. Differential gene expression patterns and the dys-regulated genes associated with clinical outcomes were analyzed. Somatic mutations were identified from the sequencing data and the deleterious mutations were predicted. Lastly, human-HBV chimeric transcripts were identified, and their distribution, potential function and expression association were analyzed.ResultsExpression profiling identified the significantly upregulated TP73 as a nodal molecule modulating expression of apoptotic genes. Approximately 2.5% of dysregulated genes significantly correlated with HCC clinical characteristics. Of the 110 identified genes, those involved in post-translational modification, cell division and/or transcriptional regulation were upregulated, while those involved in redox reactions were downregulated in tumors of patients with poor prognosis. Mutation signature analysis identified that somatic mutations in HCC tumors were mainly non-synonymous, frequently affecting genes in the micro-environment and cancer pathways. Recurrent mutations occur mainly in ribosomal genes. The most frequently mutated genes were generally associated with a poorer clinical prognosis. Lastly, transcriptome sequencing suggest that HBV replication in the tumors of HCC patients is rare. HBV-human fusion transcripts are a common observation, with favored HBV and host insertion sites being the HBx C-terminus and gene introns (in tumors) and introns/intergenic-regions (in non-tumors), respectively. HBV-fused genes in tumors were mainly involved in RNA binding while those in non-tumors tissues varied widely. These observations suggest that while HBV may integrate randomly during chronic infection, selective expression of functional chimeric transcripts may occur during tumorigenesis.ConclusionsTranscriptome sequencing of HCC patients reveals key cancer molecules and clinically relevant pathways deregulated/mutated in HCC patients and suggests that while HBV may integrate randomly during chronic infection, selective expression of functional chimeric transcripts likely occur during the process of tumorigenesis.

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Comprehensive analysis of genomic and immunological profiles in Chinese and Western hepatocellular carcinoma populations.

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