Identification of Tumor Mutation Burden and Immune Infiltrates in Hepatocellular Carcinoma Based on Multi-Omics Analysis

Abstract

We aimed to explore the tumor mutational burden (TMB) and immune infiltration in HCC and investigate new biomarkers for immunotherapy. Transcriptome and gene mutation data were downloaded from the GDC portal, including 374 HCC samples and 50 matched normal samples. Furthermore, we divided the samples into high and low TMB groups, and analyzed the differential genes between them with GO, KEGG, and GSEA. Cibersort was used to assess the immune cell infiltration in the samples. Finally, univariate and multivariate Cox regression analyses were performed to identify differential genes related to TMB and immune infiltration, and a risk prediction model was constructed. We found 10 frequently mutated genes, including TP53, TTN, CTNNB1, MUC16, ALB, PCLO, MUC, APOB, RYR2, and ABCA. Pathway analysis indicated that these TMB-related differential genes were mainly enriched in PI3K-AKT. Cibersort analysis showed that memory B cells (p = 0.02), CD8+ T cells (p = 0.09), CD4+ memory activated T cells (p = 0.07), and neutrophils (p = 0.06) demonstrated a difference in immune infiltration between high and low TMB groups. On multivariate analysis, GABRA3 (p = 0.05), CECR7 (p < 0.001), TRIM16 (p = 0.003), and IL7R (p = 0.04) were associated with TMB and immune infiltration. The risk prediction model had an area under the curve (AUC) of 0.69, suggesting that patients with low risk had better survival outcomes. Our study demonstrated for the first time that CECR7, GABRA3, IL7R, and TRIM16L were associated with TMB and promoted antitumor immunity in HCC.

Tumor Mutation Burden-Associated LINC00638/miR-4732-3p/ULBP1 Axis Promotes Immune Escape via PD-L1 in Hepatocellular Carcinoma

“…Unfortunately, however, few clinical studies have revealed the role of TMB in HCC. We and others found a significant correlation between TMB and immune infiltration in HCC (5)(6)(7). Most importantly, the PS model was significantly associated with TMB and immune infiltration.…”

“…Most importantly, TMB status was significantly associated with PS, and in other words, patients in the high-score group may have also had a high level of TMB (Figures 4B, C). In addition, the 3 most frequently mutated genes in HCC were employed as stratification factors, and therefore, the correlation between PS and OS was further investigated in the TCGA cohort 6 . The data showed that in the cohort of patients with wild-type or mutant TP53, wild-type or mutant TTN, and wild-type or mutant CTNNB1, PS still possessed clinically and statistically significant value for predicting patient prognosis (Figures 4D-I).…”

“…A detailed understanding of the mechanism underlying immune infiltration may favor precision immunotherapy in HCC. Tumor mutation burden (TMB) refers to the total number of mutations in the coding region of the evaluated gene in the tumor cell (TC) genome, which is calculated by the total number of mutations per megabase in the genome (5)(6)(7). Previous reports suggested the close association of TMB with immune infiltration, while the molecular mechanism remains inconclusive (5)(6)(7).…”

Immune checkpoint molecules are regulated by transforming growth factor (TGF)-β1-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma

“…Tissue-agnostic biomarkers such as tumour mutation burden (TMB) and MSI have been examined for cancer immunotherapy 57 - 59 . TMB has been utilised as a predictive biomarker in cancer immunotherapy in several studies 11 , 60 - 62 . Our previous study demonstrated significant association of TMB with poor clinical outcomes in HCC patients 11 .…”

Flavonoid compounds of buah merah (Pandanus conoideus Lamk) as a potent SARS-CoV-2 main protease inhibitor: in silico approach

“…The terpenoid and triterpenoid compounds are the strongest inhibitor [ 2 , 3 ]. Previous studies reported that rutin had the best inhibitory effect, even compared to the FDA-approved COVID19 antiviral (Remdesivir) [ 2 , 5 ]. This terpenoid is known to bind stably to the SARS-CoV-2 main protease receptor (PDB ID 6YNQ).…”