Risk Of HBV-related Hepatocellular Carcinoma Research Articles

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.

Hepatocellular Carcinoma and Hepatitis: Advanced Diagnosis and Management with a Focus on the Prevention of Hepatitis B-Related Hepatocellular Carcinoma.

Though the world-wide hepatitis B virus (HBV) vaccination program has been well completed for almost thirty years in many nations, almost HBV-related hepatocellular carcinoma (HCC) occurs in unvaccinated middle-aged and elderly adults. Apparently, treating 80% of qualified subjects could decrease HBV-related mortality by 65% in a short period. Nevertheless, globally, only 2.2% of CHB patients undergo antiviral therapy. The HBV markers related to HCC occurrence and prevention are as follows: the HCC risk is the highest at a baseline of HBV DNA of 6-7 log copies/mL, and it is the lowest at a baseline of an HBV DNA level of >8 log copies/mL and ≤4 log copies/mL (parabolic, and not linear pattern). The titer of an HBV core-related antigen (HBcrAg) reflecting the amount of HBV covalently closed circular DNA (ccc DNA) in the liver is related to HCC occurrence. The seroclearance of HBs antigen (HBsAg) is more crucial than HBV DNA negativity for the prevention of HCC. In terms of the secondary prevention of hepatitis B-related HCC involving antiviral therapies with nucleos(t)ide analogues (NAs), unsolved issues include the definition of the immune-tolerant phase; the optimal time for starting antiviral therapies with NAs; the limits of increased aminotransferase (ALT) levels as criteria for therapy in CHB patients; the normalization of ALT levels with NAs and the relation to the risk of HCC; and the relation between serum HBV levels and the risk of HCC. Moreover, the first-line therapy with NAs including entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) remains to be clarified. Discussed here, therefore, are the recent findings of HBV markers related to HCC occurrence and prevention, unsolved issues, and the current secondary antiviral therapy for the prevention of HBV-related HCC.

Contribution of an Asian-prevalent HLA haplotype to the risk of HBV-related hepatocellular carcinoma

Liver cancer, particularly hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), is more common in Asians than in Caucasians. This is due, at least in part, to regional differences in the prevalence of exogenous factors such as HBV; however, endogenous factors specific to Asia might also play a role. Such endogenous factors include HLA (human leukocyte antigen) genes, which are considered candidates due to their high racial diversity. Here, we performed a pancancer association analysis of 147 alleles of HLA-class I/II genes (HLA-A, B, and C/DRB1, DQA1, DQB1, DPA1, and DPB1) in 31,727 cases of 12 cancer types, including 1684 liver cancer cases and 107,103 controls. HLA alleles comprising a haplotype prevalent in Asia were significantly associated with pancancer risk (e.g., odds ratio [OR] for a DRB1*15:02 allele = 1.12, P = 2.7 × 10–15), and the associations were particularly strong in HBV-related HCC (OR 1.95, P = 2.8 × 10–5). In silico prediction suggested that the DRB1*15:02 molecule encoded by the haplotype does not bind efficiently to HBV-derived peptides. RNA sequencing indicated that HBV-related HCC in carriers of the haplotype shows low infiltration by NK cells. These results indicate that the Asian-prevalent HLA haplotype increases the risk of HBV-related liver cancer risk by attenuating immune activity against HBV infection, and by reducing NK cell infiltration into the tumor.

Hormone replacement therapy is associated with reduced hepatocellular carcinoma risk and improved survival in postmenopausal women with hepatitis B: A nationwide long-term population-based cohort study.

Postmenopausal women with hepatitis B virus (HBV) infection are more likely to have accelerated liver fibrosis, eventually advancing to liver cirrhosis or hepatocellular carcinoma (HCC). The association between sex hormones and HBV-related HCC risk is unclear. We investigated whether hormone replacement therapy (HRT) is beneficial to postmenopausal women with HBV infection. This retrospective study selected the data of 44,465patients with HBV infection between January 2000 and December 2018 from Taiwan’s National Health Insurance Research Database. After excluding patients with preexisting liver diseases, liver cirrhosis, or liver malignancies, we grouped the remaining 10,474 patients by whether they had undergone HRT for at least 3 months (n = 5,638) and whether they had not received HRT (n = 4,836). After propensity score matching, we assigned 3080 patients to an HRT cohort and matched them (1:1) with those in a non-HRT cohort. The incidence of HCC (P < 0.022) and all-cause mortality rate (P < 0.001) were lower in the HRT cohort than in the non-HRT cohort. The liver cirrhosis risk was not significantly higher in the HRT cohort (P = 0.355). HRT is associated with reduced HCC risk and improved survival outcomes but is unrelated to liver cirrhosis development in postmenopausal women.

Association of ISG20 rs4566136 polymorphism with hepatitis B virus-related hepatocellular carcinoma

Objectives: Interferon-stimulated gene 20 (ISG20) plays an important role in viral infection and cancers. This study investigated the association between ISG20 rs4566136 polymorphism with HBV-related hepatocellular carcinoma (HCC). Subjects and methods: The SNP ISG20 rs4566136 was genotyped by Sanger sequencing in 115 patients with HCC, 100 liver cirrhosis patients (LC) and 120 healthy controls (HC). Results: We observed that the frequencies of genotype ISG20 rs4566136CC and allele rs4566136C were significantly lower in HCC patients compared to LC patients and HC individuals. These results indicated that the SNP ISG20 rs4566136 was associated with HCC (HCC vs. LC: OR (95%CI) = 0.67 (0.46-0.99), p = 0.04; HCC vs. HC: OR (95%CI) = 0.2 (0.12 - 0.32), p &lt; 0.001. Patients with genotype rs4566136TT had higher AST and ALT levels, followed by patients with genotype rs4566136TC and rs4566136CC. However, the difference was not significant. Conclusion: ISG20 rs4566136 polymorphism is associated with HBV-related HCC in the Vietnamese population. Allele rs4566136C contributes to a decreased risk of HBV-related HCC. * Keywords: ISG20; SNPs; rs4566136; HBV; HCC.

Association of human leukocyte antigen-DR-DQ-DP haplotypes with the risk of hepatitis B virus-related hepatocellular carcinoma

Aim: Genetic polymorphisms of human leukocyte antigen (HLA) class II molecules are associated with chronic hepatitis B virus (HBV) infection. We aimed to investigate the impacts of HLA-II haplotypes on viral evolution and the risks of HBV-caused liver diseases. Methods: HLA-DR-DQ-DP haplotypes were estimated in 1210 healthy controls, 296 HBV clearance subjects, 301 asymptomatic hepatitis B surface antigen carriers, 770 chronic hepatitis B patients, 443 HBV-related liver cirrhosis (LC) patients, and 1037 HBV-related hepatocellular carcinoma (HCC) patients. HBV mutations were determined by sequencing. The associations of HLA-DR-DQ-DP haplotypes with viral mutations and the risks of liver diseases were assessed by multivariate logistic regression. Results: Compared to HBV-free subjects, the haplotypes CCAACG, CCGACG, TCAATA, and TCGATA were associated with decreased HCC risk, with an odds ratio (OR) [95% confidence interval (CI)] of 0.62 (0.40-0.95), 0.60 (0.39-0.92), 0.73 (0.54-0.98), and 0.58 (0.42-0.78), respectively. CCAACG, CCGACG, and TCAATA were significantly associated with decreased frequencies of the HCC-risk HBV mutations: preS1 deletion, APOBEC-signature HBV mutations in the core promoter and preS regions, A51C/T, G104C/T, and G146C/T. TCGATA and TTAACG were associated with increased LC risk, with an OR (95%CI) of 1.54 (1.03-2.30) and 2.23 (1.50-3.33), respectively. However, TCGATA and TTAACG were not consistently associated with the cirrhosis-risk HBV mutations. Conclusion: CCAACG, CCGACG, and TCAATA are inversely associated with HCC risk, possibly because they are involved in creating an immune microenvironment attenuating the generation of HCC-risk HBV mutations. TCGATA and TTAACG might predispose the polarity of immunity towards Th17 isotype related to LC.

A Genetic Variant of PPP1CB Influences Risk of Hepatitis B Virus-Related Hepatocellular Carcinoma in Han Chinese: A Pathway Based Analysis.

PurposeActivation of actin cytoskeleton remodeling is an important stage preceding cancer cell metastasis. Previous genome-wide association studies (GWAS) have identified multiple hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC)-associated risk loci. However, limited sample size or strict significance threshold of GWAS may cause HBV-related HCC risk-associated genetic loci to be undetected. We aimed to investigate the performance of the SNP rs13025377 in PPP1CB in HCC.Patients and MethodsWe performed a case–control study including 1161 cases and 1353 controls to evaluate associations between single nucleotide polymorphisms (SNPs) from 98 actin-cytoskeleton regulatory genes and risk of HBV-related HCC. The effects of SNPs on HBV-related HCC risk were assessed under logistic regression model and corrected by false discovery rate (FDR).ResultsWe found that rs13025377 in PPP1CB was significantly associated with HBV-related HCC risk [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.72~0.91, P = 4.88×10–4]. The risk allele A of rs13025377 increased PPP1CB expression levels in normal liver tissue. SNP rs4665434 was tagged by rs13025377 (r2 = 0.9) and its protective allele disrupted CTCF and Cohesin motifs. According to public datasets, PPP1CB, CTCF and Cohesin expression levels are increased in tumor tissues. Kaplan–Meier plots demonstrated that higher PPP1CB expression was significantly associated with shorter overall survival (OS). Moreover, we observed strong correlation between CTCF, Cohesin, and PPP1CB in various liver tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis confirmed that PPP1CB plays a role in HCC through actin-cytoskeleton regulation.ConclusionThus, these findings indicated that PPP1CB may be a key gene in actin-cytoskeleton regulation and rs13025377 contributes to the risk of HBV-related HCC by regulating PPP1CB expression.

New Thresholds for AFP and Des-γ-Carboxy Prothrombin in Chronic Liver Disease Depending on the Use of Nucleoside Analogs and an Integrated Nomogram.

BackgroundThe thresholds of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (PIVKA-II) when detecting hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with antiviral nucleoside analog (NA) remain controversial. A relevant integrated nomogram needs to be developed.MethodsWe enrolled a consecutive series of 5666 cases diagnosed with CHB either with or without antiviral agents and randomly allocated them to the training set (n=3966, 70.00%) and the validation set (n=1700, 30.00%).ResultsIn the training set, the levels of AFP and PIVKA-II of NA-treated patients were significantly lower than those of untreated patients. The most appropriate cut-off values of AFP and PIVKA-II were 151.40 ng/mL (a sensitivity of 39.77% and a specificity of 92.17%) and 35.50 mAU/mL (a sensitivity of 84.85% and a specificity of 69.43%) for NA-treated patients. As for BCLC-0/A HCC, the most appropriate cut-off values of AFP and PIVKA-II were 151.40 ng/mL and 32.50 mAU/mL for NA-treated patients, respectively. A logistic regression model composed of AFP, PIVKA-II and other clinical parameters to predict the risk of HBV-related HCC for NA-treated patients was established and verified to have an AUROC of 0.868 (95% CI, 0.827–0.909) for all-stage HCC and an AUROC of 0.856 (95% CI, 0.809–0.903) for BCLC-0/A HCC.ConclusionThe new detection thresholds of AFP and PIVKA-II might lead to the ability to perform early detection for hepatoma in NA-treated patients and the innovative risk prediction model is a valuable tool for identifying high-risk CHB patients.

Fine Mapping of the MHC Region Identifies Novel Variants Associated with HBV-Related Hepatocellular Carcinoma in Han Chinese.

IntroductionGenome-wide association studies identified susceptibility loci in the major histocompatibility complex region for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the causal variants underlying HBV-related HCC pathogenesis remain elusive.MethodsWith a total of 1,161 HBV-related HCC cases and 1,353 chronic HBV carriers without HCC, we imputed human leukocyte antigen (HLA) variants based on a Chinese HLA reference panel and evaluated the associations of these variants with the risk of HBV-related HCC. Conditional analyses were used to identify independent signals associated with the risk of HBV-related HCC (P false-discovery rate (FDR) <0.20). A total of 14,930 variants within the MHC region were genotyped or imputed.ResultsWe identified two variants, rs114401688 (P = 1.05 × 10−6, PFDR = 2.43 × 10−3) and rs115126566 (P = 9.04 × 10−5, PFDR = 1.77 × 10−1), that are independently associated with the risk of HBV-related HCC. Single nucleotide polymorphism (SNP) rs114401688 is in linkage disequilibrium with a previously reported SNP rs9275319. In the current study, we found that its association with HCC could be explained by HLA-DQB1*04 and HLA-DRB1*04. SNP rs115126566 is a novel risk variant and may function by regulating transcriptions of HLA-DPA1/DPB1 through enhancer-mediated mechanisms. HLA zygosity analysis showed that homozygosity at HLA-DQB1 gene is suggestively associated with a higher risk of HCC (P = 0.10) and the risk was more pronounced in the older age group (age ≥50, P = 0.03).DiscussionOur findings further the understanding of the genetic basis for HBV-related HCC predisposition in chronic HBV carriers.

Effects of genetic polymorphisms in INTS10 and their interaction with environmental factors on progression from persistent HBV infection to hepatocellular carcinoma.

Genome-wide association study recently identified a novel antiviral gene INTS10 (index rs7000921) in suppression of hepatitis B virus (HBV) replication. However, data were lacking on single nucleotide polymorphisms (SNPs) of INTS10 in the context of hepatocellular carcinoma (HCC) induced by HBV infection. Herein, we conducted a case-control study, including 737 HBV-related HCC cases and 750 persistently HBV-infected controls, to investigate the effect of INTS10 SNPs and their gene-environment interactions on HBV-related HCC. In multivariate analysis, the CT genotype of rs7000921 conferred a decreased risk of HBV-related HCC compared to the TT genotype (adjusted odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.64-0.98, p for permutation test = .038). Among the 12 tagSNPs, the rs4268139 yielded a borderline significant association with disease risk under the additive model (adjusted OR = 0.80, 95% CI = 0.63-1.00, p for permutation test = .061). Random forest model further suggested the rs7000921 and rs7822495 as the two-top ranked important SNPs, and thus a weighted genetic risk score (wGRS) was generated from these two SNPs plus rs4268139. The highest tertile of wGRS was associated with an increased risk, with an adjusted OR of 1.36 (95% CI = 1.05-1.75, p for permutation test = .016) compared to the lowest wGRS. Furthermore, an additive interaction was seen between wGRS and drinking (attributable proportion due to interaction [AP] = 0.21, 95% CI = 0.02-0.43, p = .016). The additive interaction between wGRS and smoking approached near significance (AP = 0.15, 95% CI = 0.00-0.32, p = .045). INTS10 polymorphisms may contribute to the progression from HBV infection to HCC. More importantly, INTS10 polymorphisms interact with drinking and smoking to affect the progression.

Germline Variants and Genetic Interactions of Several EMT Regulatory Genes Increase the Risk of HBV-Related Hepatocellular Carcinoma.

Epithelial-mesenchymal transition (EMT) plays an important role in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We hypothesized that germline variants in the major EMT regulatory genes (SNAIL1, ZEB1, ZEB2, TWIST1) may influence the development of HBV-related HCC. We included 421 cases of HBsAg-positive patients with HCC, 1371 cases of HBsAg-positive subjects without HCC [patients with chronic hepatitis B (CHB) or liver cirrhosis (LC)] and 618 cases of healthy controls in the case-control study. Genotype, allele, and haplotype associations in the major EMT regulatory genes were tested. Environment-gene and gene-gene interactions were analysed using the non-parametric model-free multifactor dimensionality reduction (MDR) method. The SNAIL1rs4647958T>C was associated with a significantly increased risk of both HCC (CT+CC vs. TT: OR=1.559; 95% confidence interval [CI], 1.073-2.264; P=0.020) and CHB+LC (CT+CC vs. TT: OR=1.509; 95% CI, 1.145-1.988; P=0.003). Carriers of the TWIST1rs2285681G>C (genotypes CT+CC) had an increased risk of HCC (CG+CC vs. GG: OR=1.407; 95% CI, 1.065-1.858; P=0.016). The ZEB2rs3806475T>C was associated with significantly increased risk of both HCC (P recessive =0.001) and CHB+LC (P recessive<0.001). The CG haplotype of the rs4647958/rs1543442 haplotype block was associated with significant differences between healthy subjects and HCC patients (P=0.0347). Meanwhile, the CT haplotype of the rs2285681/rs2285682 haplotype block was associated with significant differences between CHB+LC and HCC patients (P=0.0123). In MDR analysis, the combination of TWIST1rs2285681, ZEB2rs3806475, SNAIL1rs4647958 exhibited the most significant association with CHB+LC and Health control in the three-locus model. Our results suggest significant single-gene associations and environment-gene/gene-gene interactions of EMT-related genes with HBV-related HCC.

Association of PD-1.9 polymorphism with the risk of HBV-related hepatocellular carcinoma

Objective: This case-control study aimed to determine the association between PD-1.9 polymorphism and the risk of HCC in the cohort of chronic HBV-infected patients. Subject and method: Genotyping of PD-1.9 polymorphism was performed by direct sanger sequencing in 499 HBV-infected patients. Patients were assigned into two groups, including CHB (n = 193) and HCC (n=306) based on clinical manifestations. Binary logistic regression adjusted for age and gender was performed to analyze the association of PD-1.9 variant with liver disease progression applying for different genetic models. Result: The frequencies of genotype PD-1.9 TT and minor allele T were significantly higher in HCC patients compared to CHB patients; genotype PD-1.9 TT: co-dominant model, OR = 2.1 (1.01-4.3), padj=0.047 and recessive model, OR = 1.8 (1.1-3.6), padj=0.042; allele PD-1.9 T: OR = 1.3 (1.1-1.8), padj=0.029. In addition, AFP levels were significantly higher in patients with genotype PD-1.9 TT compared to CT/CC genotype. Conclusion: This study, for the first time, reveals the association between PD-1.9 variant and the risk of HCC development in chronic HBV infection.

Meta-analysis: Association between hepatitis B virus preS mutation and hepatocellular carcinoma risk.

Previous observational studies suggested that hepatitis B virus (HBV) preS mutation plays an important role in the existence of HBV-related hepatocellular carcinoma (HCC). However, the results are still debatable. With an increasing number of studies about this topic, this study employed a meta-analysis to identify the association between HBV preS mutation and HCC risk. We searched for eligible studies from PubMed, ProQuest, CINAHL, ScienceDirect and Springer databases to assess the association between HBV mutation and HCC risk. This meta-analysis was conducted using RevMan 5.3 to provide pooled estimate for odds ratio (ORs) with 95% confidence intervals (95% CIs). Twenty-one clinical studies were included in this meta-analysis study which consisted of 1738 participants with HBV-related HCC and 3740 HBsAg-positive patients without HCC. All studies used samples of Asian population. PreS deletion was the most common mutation found in all studies. We found that ORs of HBV overall preS deletion was associated with HCC (OR=3.28; 95% CI=2.32-4.65; P<.00001; random-effects model). Each preS1 and preS2 deletion was associated with increased risk of HCC, with OR 2.42 (95% CI=1.25-4.68, P=.008) and 3.36 (95% CI=2.04-5.55, P<.00001), respectively. PreS2 start codon mutation was also significantly associated with HCC risk (OR=2.47; 95% CI: 1.15-5.27; P=.02; random-effect model). The result of this meta-analysis suggested that HBV preS deletion (all, preS1 and preS2) and preS2 start codon mutation might contribute to the increased risk of HBV-related HCC.

Transcriptome-wide association study for persistent hepatitis B virus infection and related hepatocellular carcinoma.

Previous genome-wide association studies (GWAS) have identified multiple susceptible variants associated with persistent hepatitis B virus (HBV) infection. However, most of these variants are located in the noncoding regions, which make it difficult to determine the effective genes underlying these associations. We performed a two-stage study, in the first stage we integrated RNA sequencing data of liver tissues and high-density genotyping data from the Genotype-Tissue Expression (GTEx) project with our previous GWAS data to conduct a transcriptome-wide association study (TWAS) on HBV infection. Firstly, the cis-heritable genes were screened by a genetic relatedness matrix of genome-wide complex trait analysis (GCTA) from GTEx data. Then, the genetic expression of 2587 cis-heritable genes was predicted by restricted maximum likelihood (REML) of genome-wide efficient mixed-model association (GEMMA) in our GWAS data with 951 HBV carrier cases and 937 HBV cleared controls. Next, we investigated the associations between predictive expression levels and persistent HBV infection risk. Gene set enrichment analysis (GSEA) was applied to infer the function of the identified genes. To identify the causal single nucleotide polymorphisms (SNPs) of HBV infection risk, we conducted the expression quantitative trait loci (eQTL)-based stepwise logistic regression analysis in the regions around 1 Mb of these genes and validated the association between 994 health controls and 994 HBV-persistent infection cases by genotyping experiment. In the second stage, 1538 HBV-related hepatocellular carcinoma (HCC) cases and 1465 persistent HBV infection controls were collected to determine the effect of these variants on HBV-related HCC as well, which were examined by the additive model in logistic regression analysis. We identified seven genes associated with HBV infection. In the classic human leukocyte antigen (HLA) region, three novel genes BAK1, HLA-DOB and C4A (Z range from -3.95 to -3.64, P range from 7.84 × 10-5 to 2.00 × 10-4 ), as well as two genes (HLA-DPA1 and HLA-DPB1) were reported by previous GWAS. In the non-HLA region, immune related at newly identified loci, PARP9 (Z = 3.69, P = 2.20 × 10-4 ) at 3q21.1. At 22q11.21, we identified TMEM191A (Z = 3.55, P = 3.80 × 10-4 ) as a target gene in addition to the reported non-cis-heritable gene UBE2L3. After further stepwise logistic regression analysis and validation, we identified eight variants independently associated with persistent HBV infection. Among those variants, the additive model showed that two SNPs associated with HBV-related HCC risk (rs9272714 and rs9394194, OR range from 1.20 to 1.25, P range from 1.19 × 10-4 to 3.97 × 10-4 ). By integrating transcriptome data, our study not only identified new susceptibility loci of persistent HBV infection but also determined the potential target genes at reported loci, which provided insight into the genetic aetiology of persistent HBV infection and related HCC.

Prediagnostic concentrations of circulating bile acids and hepatocellular carcinoma risk: REVEAL-HBV and HCV studies.

Hepatocellular carcinoma (HCC) is the dominant histologic type of liver cancer, accounting for 75% of cases. Growing evidence suggests that the cross-talk between the gut microbiome and metabolome (ie, gut-liver axis) are related to the development of hepatic inflammation, and ultimately, HCC. Bile acids are metabolites, derived from cholesterol and synthesized in the liver, which may have a critical role in regulation of the gut-liver axis. We investigated whether prediagnostic circulating bile acids were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)-Hepatitis B Virus (HBV) and REVEAL-Hepatitis C Virus (HCV) cohorts from Taiwan. Fifteen bile acids were quantitated using liquid chromatography, from 185 cases and 161 matched controls in REVEAL-HBV and 96 cases and 96 matched controls in REVEAL-HCV. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between bile acid levels and HCC were calculated using multivariable-adjusted logistic regression. Higher levels of glycine and taurine conjugated primary bile acids were associated with a 2- to 8-fold increased risk of HBV- (eg, glycocholic acid ORQ4vsQ1 = 3.38, 95% CI: 1.48-7.71, Ptrend < .003) and HCV-related HCC (eg, OR = 8.16, 95% CI: 2.21-30.18, Ptrend < .001). However, higher levels of the secondary bile acid deoxycholic acid were inversely associated with HBV-related HCC risk (OR = 0.41, 95% CI: 0.19-0.88, Ptrend = .02). Our study provides evidence that higher concentrations of bile acids-specifically, conjugated primary bile acids-are associated with increased HCC risk. However, our study does not support the hypothesis that higher levels of secondary bile acids increase liver cancer risk; indeed, deoxycholic acid may be associated with a decreased HCC risk.

Nonreceptor protein tyrosine phosphatases (NRPTPs) gene family associates with the risk of hepatocellular carcinoma in a Chinese hepatitis B virus-related subjects.

Nonreceptor protein tyrosine phosphatases (NRPTPs) are reported to be associated with several human cancers, but their roles in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unclear. Here, we integrated bioinformatics tools, population association analyses, and biological assays to systematically screen for potentially functional single nucleotide polymorphisms (SNPs) within the 17 NRPTPs genes and evaluate the effects of candidate SNPs on the risk of HCC or persistent HBV infection. A total of 790 HBV-related HCC cases and 1454 cancer-free controls were enrolled. Controls included 711 HBV persistent carriers and 743 spontaneously recovered subjects. Results demonstrated that PTPN4 rs9308777 (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.06-1.49, P = .009) and PTPN12 rs350050 (OR = 1.26, 95% CI = 1.10-1.45, P = .001), were significantly associated with HCC risk, but not with persistent HBV infection risk. The cumulative risk effect of these two SNPs was more significantly increased the susceptibility to HCC (OR = 1.27, 95% CI = 1.14-1.41, P = 2.40 × 10-5 ). Subsequent biological assays further revealed the potential pathogenesis that PTPN4 rs9308777 might decrease the gene expression, and PTPN12 rs3750050 might promote cell proliferation by attenuating PTPN12's inhibitory activity on EGFR/ERK pathway. In summary, our integrative study highlights that PTPN4 and PTPN12 are significantly associated with HBV-related HCC risk, but do not influence persistent HBV infection. These findings shed light on the importance of the synergistic effects of regulatory and missense variants on the risk for HCC, and provide data to support personalized cancer medicine in the future.

Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma

BackgroundRecent genome-wide association studies (GWASs) have suggested several susceptibility loci of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by statistical analysis at individual single-nucleotide polymorphisms (SNPs). However, these loci only explain a small fraction of HBV-related HCC heritability. In the present study, we aimed to identify additional susceptibility loci of HBV-related HCC using advanced knowledge-based analysis.MethodsWe performed knowledge-based analysis (including gene- and gene-set-based association tests) on variant-level association p-values from two existing GWASs of HBV-related HCC. Five different types of gene-sets were collected for the association analysis. A number of SNPs within the gene prioritized by the knowledge-based association tests were selected to replicate genetic associations in an independent sample of 965 cases and 923 controls.ResultsThe gene-based association analysis detected four genes significantly or suggestively associated with HBV-related HCC risk: SLC39A8, GOLGA8M, SMIM31, and WHAMMP2. The gene-set-based association analysis prioritized two promising gene sets for HCC, cell cycle G1/S transition and NOTCH1 intracellular domain regulates transcription. Within the gene sets, three promising candidate genes (CDC45, NCOR1 and KAT2A) were further prioritized for HCC. Among genes of liver-specific expression, multiple genes previously implicated in HCC were also highlighted. However, probably due to small sample size, none of the genes prioritized by the knowledge-based association analyses were successfully replicated by variant-level association test in the independent sample.ConclusionsThis comprehensive knowledge-based association mining study suggested several promising genes and gene-sets associated with HBV-related HCC risks, which would facilitate follow-up functional studies on the pathogenic mechanism of HCC.

Role of microRNA-210-3p in hepatitis B virus-related hepatocellular carcinoma.

Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002-2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC.NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.

Association of Daily Aspirin Therapy With Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B

Antiviral therapy cannot erase hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B, and it is not indicated for most hepatitis B virus (HBV) carriers. Another effective way of reducing HCC risk needs to be developed. Aspirin may prevent cancer development, but clinical evidence in patients with HBV-related HCC remains limited. To investigate the association of daily aspirin therapy with HBV-related HCC risk. In this Taiwan nationwide cohort study, we screened 204 507 patients with chronic hepatitis B for the period January 1, 1997, to December 31, 2012. After excluding patients with confounding conditions, 2123 patients who continuously received daily aspirin for 90 or more days (treated group) were randomly matched 1:4 with 8492 patients who had never received antiplatelet therapy (untreated group) by means of propensity scores, consisting of the follow-up index date, baseline characteristics, and potentially chemopreventive drug use during follow-up. Data were analyzed from August 1 to November 30, 2018. Daily aspirin therapy during the study period. Both cumulative incidence of and hazard ratios (HRs) for HCC development were analyzed after adjusting patient mortality as a competing risk event. Of the 10 615 patients included in the analysis, 7690 (72.4%) were men; mean (SD) age was 58.8 (11.8) years. The cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group in 5 years (5.20%; 95% CI, 4.11%-6.29% vs 7.87%; 95% CI, 7.15%-8.60%; P < .001). In the multivariable regression analysis, aspirin therapy was independently associated with a reduced HCC risk (HR, 0.71; 95% CI, 0.58-0.86; P < .001). Sensitivity subgroup analyses also verified this association (all HRs <1.0). In addition, older age (HR, 1.01 per year; 95% CI, 1.00-1.02), male sex (HR, 1.75; 95% CI, 1.43-2.14), and cirrhosis (HR, 2.89; 95% CI, 2.45-3.40) were independently associated with an increased HCC risk, but nucleos(t)ide analogue (HR, 0.54; 95% CI, 0.41-0.71) or statin (HR, 0.62; 95% CI, 0.42-0.90) use was correlated with a decreased HCC risk. Daily aspirin therapy may be associated with a reduced risk of HBV-related HCC.

Interleukin-21 receptor gene polymorphism is associated with hepatitis B virus-related hepatocellular carcinoma in Chinese patients.

BackgroundWe investigated the relationship between hepatitis B virus (HBV)‐related pathogenesis and single nucleotide polymorphisms (SNPs) in interleukin‐21 (IL‐21)‐JAK‐STAT signaling pathway genes.MethodsWe used the high‐resolution melting (HRM) method to genotype five SNPs (IL‐21 rs2221903, IL‐21 rs4833837, IL‐21 receptor (IL‐21R) rs2285452, JAK3 rs3008, and STAT3 rs1053023) in 546 HBV‐infected patients and 353 healthy Chinese subjects. The HBV‐infected patients were further divided into subgroups based on the HBV‐related pathologies: chronic hepatitis B (CHB), HBV‐related liver cirrhosis (LC), and HBV‐related hepatocellular carcinoma (HCC).ResultsThere were no significant differences in the genotype and allele distributions of the five SNPs between the HBV‐infected patients and healthy subjects. The genotype and allele frequencies were similar in the two groups for IL‐21 rs2221903 (A>G, P = 0.83 and 0.67), rs4833837 (A>G, P = 0.80 and 0.49), IL‐21R rs2285452 (G>A, P = 0.25 and 0.68), STAT3 rs1053023 (A>G, P = 1.00 and 0.96), and JAK3 rs3008 (C>T, P = 0.32 and 0.54). However, patients with the IL‐21R rs2285452 AA genotype were more susceptible to HBV‐related HCC than those with the IL‐21R rs2285452 GA/GG genotype (P = 0.03, OR = 3.27, 95% CI = 1.16‐9.20). The serological marker model of “HBsAg+, HBeAg+, HBcAb+” was predominant among patients with HBV infection. However, there was no association between the genotype's distribution of the five SNPs and the serological marker models (P > 0.05).ConclusionsThese findings demonstrate that the IL‐21R rs2285452 AA genotype increases the risk of HBV‐related HCC in Chinese patients.