Risk Of HCV-related Hepatocellular Carcinoma Research Articles

Correlation of DEPDC5 rs1012068 and rs5998152 Polymorphisms with Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Emerging evidence has shown that two common genetic polymorphisms within the pleckstrin domain-containing protein 5 (DEPDC5), rs1012068 and rs5998152, may be associated with the risk of hepatocellular carcinoma (HCC), especially in those individuals chronically infected with the hepatitis C virus (HCV) or the hepatitis B virus (HBV). However, these findings have not been consistently replicated in the literature due to limited sample sizes or different etiologies of HCC. Thus, the present systematic review and meta-analysis were performed to resolve this inconsistency. The databases PubMed, Embase, Web of Science, the China National Knowledge Infrastructure, and Scopus were searched up to December 12, 2022. Data from relevant studies were pooled, and odds ratios and 95% confidence intervals were calculated. A total of 11 case-control studies encompassing 2,609 cases and 8,171 controls on rs1012068 and three encompassing 411 cases and 1,448 controls on rs5998152 were included. Results indicated that the DEPDC5 rs1012068 polymorphism did not significantly increase HCC risk in the total population (allelic model (OR = 1.32, 95% CI = 1.04-1.67, P = 0.02); the recessive model (OR = 1.42, 95% CI = 0.96-2.10, P = 0.08); the dominant model (OR = 1.43, 95% CI = 1.09-1.87, P = 0.01); the homozygous model (OR = 1.61, 95% CI = 1.01-2.57, P = 0.05); the heterozygous model (OR = 1.39, 95% CI = 1.09-1.79, P = 0.009)). Subgroup analyses based on ethnicity and etiology revealed that the rs1012068 polymorphism, under all five genetic models, was associated with increased HCC risk in Asians or in individuals with chronic HBV infection but not in individuals with chronic HCV infection. A significant association was also observed between rs5998152 and HCV-related HCC risk in Asians chronically infected with HCV under allelic, dominant, and heterozygous models. Our study suggests that the DEPDC5 rs1012068 polymorphism increases HCC risk, especially in Asians with chronic HBV infection, while the rs5998152 polymorphism increases HCC risk in Asians with chronic HCV infection.

Association of Daily Aspirin Therapy With Hepatocellular Carcinoma Risk in Patients With Chronic Hepatitis C Virus Infection

Aspirin therapy has been associated with reduced risk of colon cancer, but there is only limited evidence for its effects on risk of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We aimed to investigate the association of daily aspirin therapy with HCV-related HCC risk. In this cohort study, based on Taiwan's National Health Insurance Research Database, we screened 237,963 patients with chronic HCV infection for the period of 1997 through 2011. We excluded patients with confounding conditions and 2478 patients who continuously received daily aspirin therapy for 90 days or more (treated group) were randomly matched 1:2 with 4956 patients who had never received antiplatelet therapy (untreated group) by means of propensity scores. Cumulative incidence of, and hazard ratio (HR) for, HCC development were analyzed after we adjusted for patient mortality as a competing risk event. The cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group over 5 years (4.67%; 95% CI, 3.74%-5.59% vs 7.32%; 95% CI, 6.33%-8.30%; P<.001). In the multivariable regression analysis, aspirin therapy was independently associated with a reduced HCC risk (HR, 0.78, 95% CI, 0.64-0.95; P = .011), after adjustment for age per year, male sex, cirrhosis, liver decompensation, hyperlipidemia, statin use, and interferon therapy. Sensitivity subgroup analyses also verified this association (all HRs<1.0). In addition, older age (HR, 1.03 per year; 95% CI, 1.02-1.04), male sex (HR, 1.46; 95% CI, 1.21-1.77), and cirrhosis (HR, 3.13; 95% CI, 2.55-3.84) were independently associated with an increased HCC risk. In a nationwide cohort study in Taiwan, we found aspirin therapy to be significantly associated with a reduced risk of HCV-related HCC.

Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection.

Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.

Association between ABO blood group and HCV-related hepatocellular carcinoma risk in China.

The ABO blood group has previously been reported to be associated with risk for certain malignancies; however, data about the risks for hepatocellular carcinoma (HCC) according to blood type are limited. Thus, we conducted a retrospective case–control study to investigate whether the ABO blood group contributes to hepatitis C virus (HCV) infection–induced HCC.From January 2010 to June 2016, 447 consecutive patients with chronic HCV infection were recruited. Of these patients, 217 had HCV-related HCC, and 230 had chronic hepatitis C (CHC) without HCC. We performed multivariate logistic regression to probe the association between the ABO blood group and HCC risk.Compared with subjects with blood type O, patients with blood type A had an adjusted odds ratio (AOR) of 3.301 (95% confidence interval [CI], 1.927–5.653) for HCC after adjusting for age and gender. We found statistically significant associations between blood type A and HCC risk for both men (AOR [95% CI] = 4.192 [1.959–8.973]) and women (AOR [95% CI] = 2.594 [1.231–5.466]), and for patients aged below 70 years (<60 years: AOR [95% CI] = 3.418 [1.338–8.734]; 60–69 years: AOR [95% CI] = 3.917 [1.730–8.867]).Thus, HCC risk is associated with ABO blood type in Chinese CHC patients, and CHC patients with blood type A are more susceptible to HCV-related HCC than patients with other blood types.

From the Editor’s desk...: October 2016

Oral DAA therapy is a major breakthrough in the treatment of hepatitis C virus (HCV) infection. In this issue of the Journal, two articles raise concerns about this therapy while two other provide relatively good news. In the first of the two “alarming” studies, Reig et al. show an unexpected early tumor recurrence in patients with HCV-related hepatocellular carcinoma (HCC) undergoing DAA therapy. HCC recurrence coincides with HCV clearance. In the second study providing bad news, Conti et al. show that in patients with HCV-related cirrhosis, DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC, and patients previously treated for HCC have still a high risk of tumor recurrence, in the short term. In contrast, in a third study, Cheuk Men Cheung et al. find that DAA therapy in patients with decompensated cirrhosis leads to sustained improvement in liver function, with no evidence of increase in HCC development. Finally, The ANRS collaborative study group on hepatocellular carcinoma, by analyzing three distinct prospective cohorts, and a large number of patients, finds no increased risk of HCC recurrence after DAA therapy, in particular in those who underwent curative HCC treatment including liver transplantation. All these studies were performed in European countries. Together these studies indicate that there is an urgent need for large prospective studies, performed in different continents, evaluating the impact of DAA therapy on the risk of HCC, in particular, in patients with HCV-related cirrhosis.

Genetic variations in STAT4,C2,HLA-DRB1 and HLA-DQ associated with risk of hepatitis B virus-related liver cirrhosis.

Recent genome-wide associated studies (GWASs) have revealed several common loci associated with the risk of hepatitis B virus (HBV)- or hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We selected 15 single nucleotide polymorphisms (SNPs) identified through GWASs on HBV- or HCV-related HCC, and genotyped them in two independent Chinese cohorts of chronic HBV carriers, including 712 LC cases and 2601 controls. The association of each SNP with the risk of HBV-related LC was assessed by meta-analysis of the two cohorts. Of the 12 SNPs reported in HBV-related HCC GWASs, five SNPs (rs7574865 in STAT4, rs9267673 near C2, rs2647073 and rs3997872 near HLA-DRB1 and rs9275319 near HLA-DQ), were found to be significantly associated with the risk of HBV-related LC (rs7574865: P = 1.79 × 10−2, OR = 1.17, 95% CI = 1.03–1.34; rs9267673: P = 4.91 × 10−4, OR = 1.37, 95% CI = 1.15–1.63; rs2647073: P = 3.53 × 10−5, OR = 1.63, 95% CI = 1.29–2.06; rs3997872: P = 4.22 × 10−4, OR = 1.86, 95% CI = 1.32–2.62; rs9275319: P = 1.30 × 10−2, OR = 1.32, 95% CI = 1.06–1.64). However, among the three SNPs associated with the risk of HCV-related HCC in previous GWASs, none of them showed significant association with the risk of HBV-related LC. Our results suggested that genetic variants associated with HBV-related hepatocarcinogenesis may already play an important role in the progression from CHB to LC.