Table 1.

Most representative studies investigating the correlation between TMB and HCC outcome. The most frequently mutated genes related to high TMB are reported (>14%).

Study	Mutation Pathways	Most Frequently Mutated Genes Associated with High TMB	Population and Database
Hu et al. [23]	High TMB (>10) is associated with increased PDL1 expression, CD3+ T-cell infiltration, and high numbers of CD68+ TAMs and CD66b+ TANs. High-TMB patients display recurrence and poor overall survival after curative resection.	TP53, TSC1, CTNNB1	182 Chinese HCC patients (91.2% HBV-related etiology)
Hu et al. [35]	Low-risk cluster of patients, assessed by six costimulatory molecule gene (CMGs) signature, had a lower TMB, low frequency rate of TP53 mutation, higher immunophenoscore (IPS), IPS-CTLA4, IPS-PD1/PD-L1/PD-L2, and IPS-PD1/PD-L1/PD-L2+CTLA compared to the high-risk cluster.	TP53	50 normal samples and 374 HCC samples The Cancer Genome Atlas (TCGA)
Liu et al. [36]	The high expression of ZCCHC17 is related to AFP, histologic grade, tumor status, vascular invasion, and pathological stage. A high expression of ZCCHC17 was associated with high TMB and microsatellite instability.	TP53	374 HCC patients TCGA LIHC (hepatocellular carcinoma) project
Li et al. [37]	Probability of genetic mutations, overall survival and median survival in the high-LMRGS group were significantly shorter than in the low-LMRGS group. In the high-LMRGS group, the immune microenvironment presented more inhibitory immune cell infiltration (follicular helper T cells and regulatory T cells).	TP53, TTN, CTNNB1	TCGA-HCC dataset used as the training cohort, ICGC-LIRI-JP dataset as validation set
Yang et al. [38]	High immune cell infiltration score was characterized by enhanced activation of immune-related signaling pathways and a significantly higher TMB. Immune cell infiltration score could predict patient responses to immunotherapy independently from TMB.	n.a.	571 HCC patients The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts
Liu et al. [34]	CD39+PD-1intCD8+ TILs displayed an effector phenotype and stronger antitumor activity in high-high-affinity neoantigens (HAN) versus low-HAN group.	TP53, CTNNB1, ARID1A	56 patients with HCC in The First Affiliated Hospital of Sun Yatsen University
Mauriello et al. [33]	In cancer patients undergoing immunotherapy, a stronger correlation between TMB, number of predicted neoantigens, and survival was observed.	n.a.	115 Hepatocellular carcinoma (HCC) patients available from The Cancer Genome Atlas (TCGA)
Liu et al. [39]	Low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B) mutation was associated with a higher TMB and higher expression of HHLA2. The prognosis of HCC patients with LRP1B mutation was poor.	LRP1B, TP53, TTN, MUC16, AHNAK2, OBSCN, FLG, PCLO, HMCN1, USH2A, CSMD3, XIRP2, RYR2	361 HCC patients from TCGA 399 cases from International Cancer Genome Consortium (ICGC)
Liu et al. [40]	Higher infiltrating abundance in the high-TMB group correlated with worse OS and hazard risk for high-TMB patients in HCC. CD8+ T cells and B cells were associated with improved survival outcomes. High TMB indicated good HCC prognosis and promoted tumor immune infiltration.	TP53, TTN, CTNNB1, MUC16	376 HCC patients from The Cancer Genome Atlas (TCGA) cohort
Xie et al. [41]	The prognosis of the high-TMB group was worse than that of the low-TMB group (cutoff TMB limit = 4.9).	TP53, TTN, MUC16, CTNNB1, PCLO	374 LIHC patients were downloaded from the TCGA database through the GDC data portal 203 HCC patients from Japan were also downloaded from ICGC
Yin et al. [42]	CECR7, GABRA3, IL7R, and TRIM16L mutations were associated with TMB and immune infiltration, and promoted antitumor immunity in HCC.	TP53, TTN, CTNNB1, MUC16	374 HCC samples and 50 matched normal samples from GDC portal
Mo et al. [43]	CTNNB1 was one of the frequently mutated genes in HCC and highly associated with survival and TMB. CTNNB1 mutation was significantly associated with a better prognosis.	TP53, TTN, CTNNB1, MUC16	260 patients from LIRI-JP, 369 from LICA-FR, and 394 from LINC-JP in ICGC database
Xu et al. [44]	PD-L1 positive patients had more vascular invasion and advanced CCLC stage. PD-L1 positive patients exhibited a lower TMB compared to the PD-L1 negative group. The most frequent driver gene mutations included TP53, CTNNB1, KMT2D, AXIN1, ALK, and NOTCH1.	TP53, CTNNB1, KMT2D, AXIN1	32 patients with primary HCC who were admitted to Hospital of Guangdong Medical University
Liu et al. [45]	Identification of a specific gene expression signature useful to predict prognosis and stratify patients with different sensitivities to immunotherapy. TMB was higher in the high-risk group than in the low-risk group.	n.a.	597 HCC patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC)
Peng et al. [46]	Identification of an immune signature included seven differentially expressed IRGs (BIRC5, CACYBP, NR0B1, RAET1E, S100A8, SPINK5, and SPP1) to predict HCC patients’ survival and immunotherapy response. The high-risk group had significantly higher TMB than the low-risk group. The high-risk group had higher TMB, and immunotherapy might be more effective in the high-risk group.	TP53, CTNNB1, TTN, MUC16	372 TCGA-HCC samples were used 242 data sets downloaded from GEO (https://www.ncbi.nlm.nih.gov/geo/ accessed on 20 January 2023) database and 232 patients’ data from LIRI-JP of International Cancer Genome Consortium (ICGC) database
Xie et al. [47]	Higher TMB was associated with worse prognosis in HCC patients. Less CD8+ T-cell enrichment was found in patients with higher TMB. The poor prognosis was in accordance with higher TMB and more activated NK cells.	TP53, CTNNB1, TTN, MUC16	LIHC cohort were collected from The Cancer Genome Atlas (TCGA) database GSE14520 dataset; LIRI cohort were acquired from the International Cancer Genome Consortium (ICGC) database
Huo et al. [48]	HCC patients with high TMB had a poor prognosis, and displayed higher proportion of CD8+ T lymphocyte infiltration compared to the low-TMB group.	TP53, TTN, CTNNB1, MUC16, PCLO	801 HCC patients from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC)1 and International Cancer Genome Consortium (ICGC), LIRI-JP)

n.a. not analyzed.