HBV-related Hepatocellular Carcinoma Research Articles

Progression of chronic liver disease to hepatocellular carcinoma: implications for surveillance and management

BackgroundCurrent opinion holds that hepatocellular carcinoma (HCC) arises as a stepwise progression from chronic liver disease (CLD) to cirrhosis and then to HCC. However, some HCCs may develop in a non-cirrhotic liver, raising uncertainty about their origin.MethodsWe analysed a prospectively accrued cohort of 2592 CLD patients (median follow-up = 13 years) with no prior evidence of liver cirrhosis. To track the progression of liver fibrosis prior to HCC diagnosis, we examined serial measurements of Fib-4 (an index of liver fibrosis). We also evaluated fibrosis progression in response to antiviral treatment in patients with hepatitis C (HCV) and hepatitis B (HBV). Recognising the limitations of serologic fibrosis assessment, we correlated Fib-4 and fibrosis histology within this cohort.ResultsAmong HCC patients, 28% had no indication of cirrhosis prior to HCC diagnosis. Only 31% of HBV-related HCC cases followed the cirrhotic pathway. HCV patients who achieved sustained virological response (SVR) developed cirrhosis approximately 7 years before HCC diagnosis.ConclusionsOur analysis challenges the notion of cirrhosis as an obligatory stage of HCC development in CLD patients. We affirm HBV’s direct oncogenic potential and find that achieving SVR does not universally prevent HCC development. Our findings have major implications for HCC surveillance.

Metabolic dysfunction-associated fatty liver disease increases the risk of complications after radical resection in patients with hepatocellular carcinoma

Background and aimsThe prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) in hepatocellular carcinoma (HCC) patients is increasing, yet its association with postoperative complications of HCC remains unclear. The aim of this study was to investigate the impact of MAFLD on complications after radical resection in HCC patients.MethodsPatients with HCC who underwent radical resection were included. Patients were stratified into MAFLD group and non-MAFLD group. Clinical features and post-hepatectomy complications were compared between the two groups, and logistic regression analysis was used to determine independent risk factors associated with post-hepatectomy complications.ResultsAmong the 936 eligible patients with HCC who underwent radical resection, concurrent MAFLD was diagnosed in 201 (21.5%) patients. Compared to the non-MAFLD group, the MAFLD group exhibited a higher incidence of complications, including infectious and major complications after radical resection in HCC patients. The logistic regression analysis found that MAFLD was an independent risk factor for complications, including infectious and major complications in HCC patients following radical resection (OR 1.565, 95%CI 1.109–2.343, P = 0.012; OR 2.092, 95%CI 1.386–3.156, P < 0.001; OR 1.859, 95% CI 1.106–3.124, P = 0.019; respectively). Subgroup analysis of HBV-related HCC patients yielded similar findings, and MAFLD patients with type 2 diabetes mellitus (T2DM) exhibited a higher incidence of postoperative complications compared to those without T2DM (all P < 0.05).ConclusionsConcurrent MAFLD was associated with an increased incidence of complications after radical resection in patients with HCC, especially MAFLD with T2DM.

Apolipoprotein H-based prognostic risk correlates with liver lipid metabolism disorder in patients with HBV-related hepatocellular carcinoma

Background/Aim: Chronic hepatitis B patients often develop concomitant fatty liver disease, which is associated with increased risk of liver cirrhosis and hepatocarcinoma. Our previous studies have shown that apolipoprotein H (APOH) levels are gradually decreased in patients with chronic HBV infection at different stages of disease progression, and APOH deficiency disrupted hepatic lipid metabolism and caused fatty liver. We focus on the relationship between APOH and hepatocellular carcinoma (HCC) in the context of chronic HBV infection. Methods and resultsAPOH was downregulated at the transcriptional level in HBV-related HCC patients from open-source human liver transcriptome databases, and relatively high expression of APOH might be a favourable prognostic marker in HCC. APOH downregulation was positively associated with tumour grade and HCC subtypes. The analysis result of CHCC-HBV database showed that APOH-associated differential expression genes (DEGs) enriched in lipid metabolic pathways and downregulated APOH correlated with macrophage, neutrophil and CD8 T cell infiltration levels. Next, in vitro experiments were performed and APOH gene was silenced in HepG2.2.15 cells, an HBV producing human HCC cells. Further transcriptomic assay and analysis revealed the DEGs were enriched in cholesterol metabolism. The subsequent RT-qPCR experiments identified that CYP7A1 expression was higher upregulated in APOH silencing HepG2.2.15 cells than vehicle control cells (p < 0.05). Finally, demographic data of patients with HBV-related HCC were enrolled, and serum APOH levels were analysed using ELISA. Serum APOH levels were significantly lower in patients with HCC than in healthy controls (p < 0.05), and positively correlated with triglyceride level in healthy controls (p < 0.05). In HBV-HCC patients, serum APOH levels were positively correlated with albumin levels and negatively correlated with alkaline phosphatase (ALP), total bilirubin, and INR levels (p < 0.05). ConclusionAPOH downregulation disrupted liver lipid metabolism to potentially affect the overall survival in patients with HBV-related HCC.

Preoperative Antiviral Therapy and Long-Term Outcomes for Hepatitis B Virus-Related Hepatocellular Carcinoma After Curative Liver Resection: A Multicenter Analysis.

To examine the association of the history of preoperative antiviral therapy (AVT) with the tumor recurrence and overall survival in HBV-related HCC patients undergoing curative-intent hepatectomy. Patients who underwent curative-intent hepatectomy for HBV-related HCC between 2014 and 2019 at 4 Chinese hospitals were analyzed. Patients were categorized as having undergone preoperative antiviral therapy (AVT) > 1 year or without antiviral therapy (non-AVT). Patient clinical features, short-term outcomes, overall survival (OS), and time-to-recurrence (TTR) were also compared. Multivariate Cox regression analysis was performed to identify the impact of preoperative AVT on the OS and TTR. Among the 565 patients, 190 (33.6%) underwent continuous AVT > 1 year before surgery. Patients in the non-AVT group were more likely to have worse liver function and more advanced tumor pathological characteristics than those in the AVT group. Postoperative morbidity and mortality rates were comparable between the two groups. Multivariate analyses revealed that a preoperative HBV viral level ≥ 2000 IU/mL was independently associated with poorer TTR (hazard ratio, 1.328; 95% CI, 1.049-1.682) and preoperative AVT was a protective factor for OS (hazard ratio, 0.691; 95% CI, 0.484-0.986). A high preoperative HBV DNA level was an independent risk factor for tumor recurrence. Preoperative AVT > 1 year was associated with better OS and a reduced incidence of tumor recurrence by inhibiting the preoperative level of HBV DNA.

Discovery and mechanistic study of Imperatorin that inhibits HBsAg expression and cccDNA transcription.

Chronic hepatitis B virus (HBV) infection remains a significant global health challenge due to its link to severe conditions like HBV-related cirrhosis and hepatocellular carcinoma (HCC). Although current treatments effectively reduce viral levels, they have limited impact on certain HBV elements, namely hepatitis B surface antigen (HBsAg) and covalently closed circular DNA (cccDNA). This highlights the urgent need for innovative pharmaceutical and biological interventions that can disrupt HBsAg production originating from cccDNA. In this study, we identified a natural furanocoumarin compound, Imperatorin, which markedly inhibited the expression of HBsAg from cccDNA, by screening a library of natural compounds derived from Chinese herbal medicines using ELISA assay and qRT-PCR. The pharmacodynamics study of Imperatorin was explored on HBV infected HepG2-NTCP/PHHs and HBV-infected humanized mouse model. Proteome analysis was performed on HBV infected HepG2-NTCP cells following Imperatorin treatment. Molecular docking and bio-layer interferometry (BLI) were used for finding the target of Imperatorin. Our findings demonstrated Imperatorin remarkably reduced the level of HBsAg, HBV RNAs, HBV DNAand transcriptional activity of cccDNA both in vitro and in vivo. Additionally, Imperatorin effectively restrained the actions of HBV promoters responsible for cccDNA transcription. Mechanistic study revealed that Imperatorin directly binds to ERK and subsequently interfering with the activation of CAMP response element-binding protein (CREB), a crucial transcriptional factor for HBV and has been demonstrated to bind to the PreS2/S and X promoter regions of HBV. Importantly, the absence of ERK could nullify the antiviral impact triggered by Imperatorin. Collectively, the natural compound Imperatorin may be an effective candidate agent for inhibiting HBsAg production and cccDNA transcription by impeding the activities of HBV promoters through ERK-CREB axis.

Serum β-klotho is a potential biomarker for the progression of hepatitis B virus-related liver diseases.

Hepatitis B virus (HBV) infection is a global epidemic that can lead to several liver diseases, seriously affecting people's health. This study aimed to investigate the clinical potential of serum β-klotho (KLB) as a promising biomarker in HBV-related liver diseases. This study enrolled 30 patients with chronic hepatitis B (CHB), 35 with HBV-related cirrhosis, 66 with HBV-related hepatocellular carcinoma (HCC), and 48 healthy individuals. ELISA measured the levels of serum KLB in the four groups. We then compared the differences in serum KLB levels among the groups and analyzed the relationship between serum KLB and routine clinical parameters. The concentrations of serum KLB levels were increased sequentially among the healthy subjects, the HBV-related CHB group, the HBV-related cirrhosis group, and the HBV-related HCC group (p < 0.05). Expression of KLB was positively correlated with alpha-fetoprotein (AFP), total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl-transferase, alkaline phosphatase, total bile acid, serum markers for liver fibrosis, ascites, cirrhosis, splenomegaly, and model for end-stage liver disease sodium, while negatively correlated with platelet count, albumin, and prothrombin activity (p < 0.05). In addition, serum KLB has better sensitivity in diagnosing HCC than AFP, and serum KLB combined with AFP has higher sensitivity and specificity than AFP alone in diagnosing HCC. Serum KLB level is associated with the severity of HBV-related liver diseases and has important diagnostic value for HCC. Therefore, it could be a predictive biomarker for monitoring disease progression.

The Adaptive Immune Response in Hepatitis B Virus-Associated Hepatocellular Carcinoma Is Characterized by Dysfunctional and Exhausted HBV-Specific T Cells.

This systematic review investigates the immunosuppressive environment in HBV-associated hepatocellular carcinoma (HCC), characterized by dysfunctional and exhausted HBV-specific T cells alongside an increased infiltration of HBV-specific CD4+ T cells, particularly regulatory T cells (Tregs). Heightened expression of checkpoint inhibitors, notably PD-1, is linked with disease progression and recurrence, indicating its potential as both a prognostic indicator and a target for immunotherapy. Nevertheless, using PD-1 inhibitors has shown limited effectiveness. In a future perspective, understanding the intricate interplay between innate and adaptive immune responses holds promise for pinpointing predictive biomarkers and crafting novel treatment approaches for HBV-associated HCC.

Fonction de l'ARNnc exosomal HEIH dans le carcinome hépatocellulaire associé au virus de l'hépatite B

Long non-coding RNA-HEIH (lncRNA-HEIH) is a potential biomarker for patients with hepatocellular carcinoma (HCC), but exosomal lncRNA-HEIH in patients with hepatitis B virus-associated HCC (B-HCC) is unclear. This study aimed to investigate the expression of exosomal lncRNA-HEIH in B-HCC patients and explore its clinical significance. We collected blood samples from 60 B-HCC patients, 60 non-hepatitis virus-associated HCC (N-HCC) patients, and 50 healthy volunteers. Exosomal lncRNA-HEIH levels were measured by real-time PCR and analyzed for their correlation with patient prognosis using Kaplan-Meier analysis. Multivariate COX regression analysis was conducted to identify factors affecting patient outcomes. The effects of lncRNA-HEIH on carcinogenesis were also investigated by constructing a Huh7 cell line stably expressing the hepatitis B virus. In the B-HCC group, there was a positive correlation between hepatitis B virus and exosomal lncRNA-HEIH. The 5-year survival rate of the exosomal lncRNA-HEIH high-expression group was significantly lower than that of the low-expression group in the B-HCC group, but not in the N-HCC group. Exosomal lncRNA-HEIH level was related to the TNM stage, lymph node metastasis and AFP. Exosomal lncRNA-HEIH level was independent risk factors for poor prognosis in B-HCC patients. In Huh7-HBV cells, lncRNA-HEIH level was significantly higher than in control, and the migration capacity of Huh7-HBV cells decreased significantly after down-regulating lncRNA-HEIH. Our findings suggest that exosomal lncRNA-HEIH is abnormally expressed and closely related to poor prognosis in B-HCC patients, indicating its potential as a diagnostic and therapeutic target for HBV-associated HCC.

Leptin receptor Gln223Arg and Lys109Arg polymorphisms may be associated with HBV-related hepatocellular carcinoma risk: A system review and meta-analysis.

Increasing evidence has suggested a strong association of hepatocellular carcinoma (HCC) susceptibility and Gln223Arg (rs1137101) and Lys109Arg (rs1137100) polymorphisms in leptin receptor (LEPR) genes. To provide a quantitative assessment for such correlation, we reviewed all related systems and conducted meta-analysis for case and control researches. A literature search of Web of Science, EMBASE, PubMed, Scopus as well as China National Knowledge Infrastructure databases was collected. 95% confidence intervals (95% CIs) together with odds ratios (ORs) were calculated. Five case-control researches consisting of 1323 cases and 1919 control cases were incorporated into meta-analysis. Researches indicated A-allelic and AA genotype of rs1137101 were substantially related to boosted susceptibility of hepatitis B virus (HBV)-related HCC (mutant model, OR = 1.81, 95% CI = 1.36-2.41, p < .001; allelic model, OR = 1.55, 95% CI = 1.32-1.83, p < .001). On the contrary, we observed GG genotype of rs1137101 substantially related to reduced risk of HBV-related HCC (wild model, OR 0.59, 95%CI = 0.46-0.75, p < .001). We observed AA genotype of rs1137100 relevant to boosted HCC risk (mutant model, OR = 1.51, 95%CI = 1.14-2.01, p = .005) as well as in those with HBV-related HCCs (homozygous model, OR = 2.12, 95%CI = 1.49-3.02, p < .001; mutant model, OR = 1.67, 95%CI = 1.23-2.26, p = .001). G-allele and AA genotype of rs1137101 might be in connection with boosted HBV-related HCC susceptibility, and wild-type GG genotype might prevent diseases. AA genotype of rs1137100 might also improve HBV-related HCC susceptibility. Such conclusions ought to be validated by larger and better-designed researches.

Impact of hepatic inflammation and fibrosis on the recurrence and long-term survival of hepatitis B virus-related hepatocellular carcinoma patients after hepatectomy

BackgroundUnderlying liver disease is correlated with hepatocellular carcinoma (HCC) development in patients with hepatitis B virus (HBV) infection. However, the impact of hepatic inflammation and fibrosis on the patients’ prognoses remains unclear.MethodsThe clinicopathological data of 638 HBV-infected patients with early-stage HCC between 2017 and 2019 were prospectively collected. Hepatic inflammation and fibrosis were evaluated by experienced pathologists using the Scheuer score system. Survival analysis was analyzed using the Kaplan–Meier analysis.ResultsApplication of the Scheuer scoring system revealed that 50 (7.9%), 274 (42.9%), and 314 (49.2%) patients had minor, intermediate, and severe hepatic inflammation, respectively, and 125 (15.6%), 150 (23.5%), and 363 (56.9%) patients had minor fibrosis, advanced fibrosis, and cirrhosis, respectively. Patients with severe hepatitis tended to have a higher rate of HBeAg positivity, higher HBV-DNA load, elevated alanine aminotransferase (ALT) levels, and a lower proportion of capsule invasion (all Pp < 0.05). There were no significant differences in the recurrence-free and overall survival among the three groups (P = 0.52 and P = 0.66, respectively). Patients with advanced fibrosis or cirrhosis had a higher proportion of HBeAg positivity and thrombocytopenia, higher FIB-4, and larger tumor size compared to those with minor fibrosis (all P < 0.05). Patients with minor, advanced fibrosis, and cirrhosis had similar prognoses after hepatectomy (P = 0.48 and P = 0.70). The multivariate analysis results indicated that neither hepatic inflammation nor fibrosis was an independent predictor associated with prognosis.ConclusionsFor HBV-related HCC patients receiving antiviral therapy, hepatic inflammation and fibrosis had little impact on the post-hepatectomy prognosis.

MiRNA‑mRNA network contributes to HBV‑related hepatocellular carcinoma via immune infiltration induced by GRB2.

Chronic hepatitis B virus (HBV) infection is a critical causative factor in the tumorigenesis and progression of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) serve a critical role in the process of viral infection. However, there has been insufficient evaluation of HBV-associated miRNA-mRNA regulatory networks in HCC. The differential expression levels of miRNAs were compared in HBV-associated HCC tumor and normal tissues using the Gene Expression Omnibus database. The present study evaluated potential target genes of differentially expressed miRNAs using protein-protein interaction network, hub gene, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment and immune infiltration analysis. A total of five miRNAs and seven target genes were identified in the HBV-associated miRNA-mRNA network. miRNA-93 could positively regulate the growth factor receptor bound protein 2 (GRB2) gene, while there was a positive correlation between GRB2 and cancer immune infiltrate function in Tumor Immune Estimation Resource. Collectively, the present study investigated the miRNA-mRNA regulatory network in HCC with HBV infection and showed that miRNA-93 positively regulated immune infiltration-related GRB2. Restoring GRB2 may be a candidate strategy for the treatment of HBV-related HCC.

Effect of HBV DNA load on the safety and prognosis of systematic therapy in advanced hepatocellular carcinoma

Objective: To study the effect of hepatitis B virus (HBV) infection on the occurrence of liver damage, HBV reactivation (HBVr) and the influence of HBVr on the prognosis of patients with advanced hepatocellular carcinoma (HCC) receiving systemic therapy. Methods: The clinical data of 403 patients with HBV-related HCC at the Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University et al, from July 2018 to December 2020 were collected. The incidence of liver damage and HBVr during systematic therapy, and the influence of HBVr on survival prognosis were analyzed. Results: Of the 403 patients, 89.1% were male (n=359), with a median age of 51 years (51.5±12.1). Before propensity score matching (PSM), the proportion of patients with cirrhosis, TNM and advanced BCLC stage was higher in high HBV-DNA (baseline HBV-DNA>1000 U/ml, n=147) group comparing with the low HBV-DNA (baseline HBV DNA≤1000 u/ml, n=256) group (P<0.05). There was no significant difference in baseline indexes between the two groups after PSM. In 290 patients after PSM, there was no significant difference in the incidence of liver damage and HBVr between high HBV-DNA group and low HBV-DNA group (P>0.05). Survival analysis was performed on 169 patients with survival data, the median overall survival (OS) was found to be 11.49 months (95%CI: 7.77-12.89) and 16.65 months (95%CI: 10.54-21.99, P=0.008) in the high and low HBV-DNA groups, respectively. And median progression-free survival (PFS) was 7.41 months (95%CI: 5.06-8.67) and 10.55 months (95%CI: 6.72-13.54, P=0.038), respectively, with a statistically significant difference. There were no differences in overall survival (OS) and progression-free survival (PFS) between patients with and without HBVr and those with or without liver damage (P>0.05). Conclusions: HBV-DNA levels above 1 000 U/ml before systemic therapy do not increase the risk of liver damage or HBVr during systemic therapy in patients with HBV-related hepatocellular carcinoma, and such patients can safely receive systemic therapy.

Hepatocellular carcinoma surveillance among people living with hepatitis B in Senegal (SEN-B): insights from a prospective cohort study

Chronic hepatitis B virus (HBV) infection is the predominant cause of hepatocellular carcinoma in west Africa, yet data on the incidence of HBV-related hepatocellular carcinoma remain scarce. We aimed to describe the uptake and early outcomes of systematic ultrasound-based hepatocellular carcinoma screening in SEN-B, which is a prospective HBV cohort in Senegal. In this prospective cohort study, we included treatment-naive, HBsAg-positive individuals who were referred to the two infectious diseases clinics (the Department of Tropical and Infectious Diseases and Ambulatory Treatment Center) at Fann University Hospital of Dakar, Senegal, between Oct 1, 2019, and Oct 31, 2022. All participants resided within the Dakar region. Participants underwent abdominal ultrasound, transient elastography, and clinical and virological assessments at inclusion and every 6 months. Liver lesions at least 1 cm in diameter on ultrasound were assessed using four-phase CT, MRI, or liver biopsy. Adherence to hepatocellular carcinoma surveillance was measured using the proportion of time covered, calculated by dividing the cumulative months covered by abdominal ultrasound examinations by the overall follow-up time, defined as the number of months from the date of cohort entry until the last recorded visit, hepatocellular carcinoma diagnosis, or death. Optimal adherence was defined as a proportion of time covered of 100%. Overall, 755 (99·6%) of 758 participants had at least one abdominal ultrasound performed. The median age of the enrolled participants was 31 years (IQR 25-39), 355 (47·0%) of 755 participants were women, and 82 (10·9%) had a family history of hepatocellular carcinoma. 15 (2·0%) of 755 individuals were HBeAg positive, 206 (27·3%) of 755 individuals had HBV DNA of more than 2000 IU/mL, and 27 (3·6%) of 755 had elastography-defined liver cirrhosis. Of ten (1·3%) participants with a focal lesion at least 1 cm at initial assessment, CT or MRI ruled out hepatocellular carcinoma in nine, whereas imaging and subsequent liver biopsy confirmed one patient with hepatocellular carcinoma. Two further patients with hepatocellular carcinoma were diagnosed at study presentation due to the presence of portal thrombosis on ultrasound. Excluding the three participants with hepatocellular carcinoma identified at baseline, 752 participants were eligible for screening every 6 months. Median follow-up time was 12 months (IQR 6-18) and the median number of ultrasounds per patient was 3 (2-4). During 809·5 person-years of follow-up, one incident hepatocellular carcinoma was reported, resulting in an incidence rate of 1·24 cases per 1000 person-years (95% CI 0·18-8·80). Overall, 702 (93·0%) of 755 participants showed optimal hepatocellular carcinoma surveillance, but this proportion decreased to 77·8% (42 of 54 participants) after 24 months. Hepatocellular carcinoma screening is feasible in HBV research cohorts in west Africa, but its longer-term acceptability needs to be evaluated. Long-term hepatocellular carcinoma incidence data are crucial for shaping tailored screening recommendations. Swiss National Science Foundation, the Swiss Cancer Research Foundation, the National Cancer Institute, and Roche Diagnostics. For the French translation of the abstract see Supplementary Materials section.

STUDY ON STAT6 rs324015 POLYMORPHISM IN HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA PATIENTS

Objectives: To determine the genotype frequency of the STAT6 rs324015 polymorphism and its association with cancer risk in hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC) patients. Methods: A cross-sectional descriptive study on 118 HBV-related HCC patients, compared to 86 HBV-related cirrhosis patients and 195 healthy people at 108 Military Central Hospital, Military Hospital 103, and Can Tho General Hospital from July 2017 to August 2020. Polymorphism analysis of the STAT6 rs324015 gene was conducted from peripheral blood samples of subjects using the Sanger sequencing method at Apical Scientific Sequencing Company (Malaysia). Results: The AG/GA heterozygous genotype of the STAT6 rs324015 polymorphism accounted for the highest rate in HCC patients at 51.7%, higher than the corresponding index in the cirrhosis group at 39.5%, and healthy people (48.2%); the GG genotype was the highest in cirrhosis patients (40.7%), the difference was not statistically significant, p &gt; 0.05. Conclusion: STAT6 rs324015 polymorphism is not associated with cancer risk in patients with HBV-related HCC.

Association between novel genetic variants of Notch signaling pathway genes and survival of hepatitis B virus-related hepatocellular carcinoma.

Although the Notch pathway plays an important role in formation and progression of hepatocellular carcinoma (HCC), few studies have reported the associations between functional genetic variants and the survival of hepatitis B virus (HBV)-related HCC. In the present study, we performed multivariable Cox proportional hazard regression analysis to evaluate associations between 36,101 SNPs in 264 Notch pathway-related genes and overall survival (OS) of 866 patients with HBV-related HCC. It was found that three independent SNPs (NEURL1B rs4868192, CNTN1 rs444927 and FCER2 rs1990975) were significantly associated with the HBV-related HCC OS. The number of protective genotypes (NPGs) were significantly associated with better survival in a dose-response manner (ptrend <0.001). Compared with the model with sole clinical factors, the addition of protective genotypes to the predict models significantly increased the AUC, i.e., from 72.72% to 75.13% (p = 0.002) and from 72.04% to 74.76 (p = 0.004) for 3-year and 5-year OS, respectively. The expression quantitative trait loci (eQTL) analysis further revealed that the rs4868192 C allele was associated with lower mRNA expression levels of NEURL1B in the whole blood (p = 1.71 × 10-3), while the rs1990975 T allele was correlated with higher mRNA expression levels of FCER2 in the whole blood and normal liver tissues (p = 3.51 × 10-5 and 0.033, respectively). Three potentially functional SNPs of NEURL1B, CNTN1 and FCER2 may serve as potential prognostic biomarkers for HBV-related HCC.

Integrating transcriptomics, glycomics and glycoproteomics to characterize hepatitis B virus-associated hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) ranks as the third most common cause of cancer related death globally, representing a substantial challenge to global healthcare systems. In China, the primary risk factor for HCC is the hepatitis B virus (HBV). Aberrant serum glycoconjugate levels have long been linked to the progression of HBV-associated HCC (HBV-HCC). Nevertheless, few study systematically explored the dysregulation of glycoconjugates in the progression of HBV-associated HCC and their potency as the diagnostic and prognostic biomarker.MethodsAn integrated strategy that combined transcriptomics, glycomics, and glycoproteomics was employed to comprehensively investigate the dynamic alterations in glyco-genes, N-glycans, and glycoproteins in the progression of HBV- HCC.ResultsBioinformatic analysis of Gene Expression Omnibus (GEO) datasets uncovered dysregulation of fucosyltransferases (FUTs) in liver tissues from HCC patients compared to adjacent tissues. Glycomic analysis indicated an elevated level of fucosylated N-glycans, especially a progressive increase in fucosylation levels on IgA1 and IgG2 determined by glycoproteomic analysis.ConclusionsThe findings indicate that the abnormal fucosylation plays a pivotal role in the progression of HBV-HCC. Systematic and integrative multi-omic analysis is anticipated to facilitate the discovery of aberrant glycoconjugates in tumor progression.

Identification of Two Distinct Immune Subtypes in Hepatitis B Virus (HBV)-Associated Hepatocellular Carcinoma (HCC).

HBV is the most common risk factor for HCC development, accounting for almost 50% of cases worldwide. Despite significant advances in immunotherapy, there is limited information on the HBV-HCC tumor microenvironment (TME), which may influence the response to checkpoint inhibitors. Here, we characterize the TME in a unique series of liver specimens from HBV-HCC patients to identify who might benefit from immunotherapy. By combining an extensive immunohistochemistry analysis with the transcriptomic profile of paired liver samples (tumor vs. nontumorous tissue) from 12 well-characterized Caucasian patients with HBV-HCC, we identified two distinct tumor subtypes that we defined immune-high and immune-low. The immune-high subtype, seen in half of the patients, is characterized by a high number of infiltrating B and T cells in association with stromal activation and a transcriptomic profile featuring inhibition of antigen presentation and CTL activation. All the immune-high tumors expressed high levels of CTLA-4 and low levels of PD-1, while PD-L1 was present only in four of six cases. In contrast, the immune-low subtype shows significantly lower lymphocyte infiltration and stromal activation. By whole exome sequencing, we documented that four out of six individuals with the immune-low subtype had missense mutations in the CTNNB1 gene, while only one patient had mutations in this gene in the immune-high subtype. Outside the tumor, there were no differences between the two subtypes. This study identifies two distinctive immune subtypes in HBV-associated HCC, regardless of the microenvironment observed in the surrounding nontumorous tissue, providing new insights into pathogenesis. These findings may be instrumental in the identification of patients who might benefit from immunotherapy.

The significance of m6A RNA methylation regulators in diagnosis and subtype classification of HBV-related hepatocellular carcinoma.

In recent years, abnormal m6A alteration in hepatocellular carcinoma (HCC) has been a focus on investigating the biological implications. In this study, our objective is to determine whether m6A modification contributes to the progression of HBV-related HCC. To achieve this, we employed a random forest model to screen top 8 characteristic m6A regulators from 19 candidate genes. Subsequently, we developed a nomogram model that utilizes these 8 characteristic m6A regulators to predict the prevalence of HBV-related HCC. According to decision curve analysis, patients may benefit from the nomogram model. The clinical impact curves exhibited a robust predictive capability of the nomogram models. Additionally, consensus molecular subtyping was employed to identify m6A modification patterns and m6A-related gene signature. The quantification of immune cell subsets was accomplished through the implementation of ssGSEA algorithms. PCA algorithms were developed to compute the m6A score for individual tumors. Two distinct m6A modification patterns, namely cluster A and cluster B, exhibited significant correlations with distinct immune infiltration patterns and biological pathways. Notably, patients belonging to cluster B demonstrated higher m6A scores compared to those in cluster A, as determined by the m6A score metric. Furthermore, the expression of IGFBP3 proteins was validated through immunofluorescence, revealing their pronounced lower expression in tumor tissues. In summary, our study underscores the importance of m6A modification in the advancement of HBV-related HCC. This research has the potential to yield novel prognostic biomarkers and therapeutic targets for the identification of HBV-related HCC.

Risk of HBV reactivation in HCC patients undergoing combination therapy of PD-1 inhibitors and angiogenesis inhibitors in the antiviral era

BackgroundAlthough routine antiviral therapy has been implemented in HCC patients, the risk of HBV reactivation (HBVr) remains with the use of programmed cell death-1(PD-1) blockade‐based combination immunotherapy and the relevant risk factors are also unclear. Therefore, we aimed to identify the incidence and risk factors of HBVr in HCC patients undergoing combination therapy of PD-1 inhibitors and angiogenesis inhibitors and concurrent first-line antivirals.MethodsWe included a total of 218 HBV-related HCC patients with first-line antivirals who received PD-1 inhibitors alone or together with angiogenesis inhibitors. According to the anti-tumor therapy modalities, patients were divided into PD-1 inhibitors monotherapy group (anti-PD-1 group) and combination therapy group (anti-PD-1 plus angiogenesis inhibitors group). The primary study endpoint was the incidence of HBVr.ResultsHBVr occurred in 16 (7.3%) of the 218 patients, 2 cases were found in the anti-PD-1 group and the remaining 14 cases were in the combination group. The Cox proportional hazard model identified 2 independent risk factors for HBVr: combination therapy (hazard ratio [HR], 4.608, 95%CI 1.010–21.016, P = 0.048) and hepatitis B e antigen (HBeAg) positive (HR, 3.695, 95%CI 1.246–10.957, P = 0.018). Based on the above results, we developed a simple risk-scoring system and found that the high-risk group (score = 2) developed HBVr more frequently than the low-risk group (score = 0) (Odds ratio [OR], 17.000, 95%CI 1.946–148.526, P = 0.01). The area under the ROC curve (AUC-ROC) was 7.06 (95%CI 0.581–0.831, P = 0.006).ConclusionHBeAg-positive patients receiving combination therapy have a 17-fold higher risk of HBVr than HBeAg-negative patients with PD-1 inhibitors monotherapy.

Changing etiology and epidemiology of hepatocellular carcinoma: Asia and worldwide.

Approximately 80% of hepatocellular carcinoma (HCC) cases arise in sub-Saharan Africa and Eastern Asia, following a similarly high prevalence of chronic hepatitis B virus (HBV) carriers in these regions. The etiology and epidemiology of HCC have recently changed worldwide. Although HBV infection is the main contributor to HCC development, a slow but continuous decline in HBV infection rates has been reported since 1990. Owing to the widespread use of direct-acting antivirals, the incidence of hepatitis C virus-related HCC has remarkably decreased in Japan and European countries. In Korea, Taiwan, and Singapore, the incidence of HBV-related HCC has significantly decreased owing to vaccination against HBV. Globally, while HBV accounted for more than half of HCCs in 1990, this had decreased to 42% in 2019. In contrast, the proportion of patients with alcoholic- and nonalcoholic steatohepatitis (NASH) increased from 13% to 18% and from 5% to 6%, respectively. NASH-related HCC has characteristics that differ from those of virus-associated HCC. Compared with other etiologies, patients with NASHassociated HCC are older, have a higher body mass index, and have higher rates of type 2 diabetes mellitus, hypertension, hyperlipidemia, and cardiovascular disease. Nonalcoholic fatty liver disease (NAFLD)-associated HCC is also known to develop in the absence of cirrhosis, unlike alcohol-related and autoimmune liver diseases. Because patients with NAFLD usually have diabetes or obesity, surveying this population is challenging. Optimal selection of the target population and surveillance tools among patients with NAFLD needs to be determined.