Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs.
Biomarkers, Tumor/genetics/metabolism ; Carcinoma, Hepatocellular/*etiology ; Hepacivirus/genetics/*pathogenicity ; Hepatitis C/complications/pathology/virology ; Humans ; Liver Neoplasms/*etiology ; Risk

OBJECTIVETo investigate the association of genetic polymorphisms in glutathione S-transferases(GST) M1 with hepatitis beta-related hepatocellular carcinoma (HCC).

METHODSGenomic DNA was isolated from peripheral blood of HBsAg carriers, including 91 cases of HCC, 58 liver cirrhosis(LC), 63 chronic hepatitis B(CHB), and 134 normal controls. GSTM1 genotypes were detected by multiplex PCR.

RESULTSThe null genotype of GSTM1 was significantly frequent in patients with HCC compared with controls (P<0.05), but there were no significant differences in frequency of GSTM1 null genotype among patients with liver cirrhosis, chronic hepatitis B and normal controls. Subjects carrying null genotypes of GSTM1 had higher risk of developing HCC compared with those carrying positive genotype (OR=1.81.95% CI=1.05 approximately equals 3.12).

CONCLUSIONThe GSTM1-null genotype may be associated with an increased risk of HCC, but not of CHB and LC.

Adult ; Carcinoma, Hepatocellular ; etiology ; genetics ; virology ; Female ; Genotype ; Glutathione Transferase ; genetics ; Hepatitis B, Chronic ; complications ; genetics ; Humans ; Liver Cirrhosis ; etiology ; genetics ; virology ; Liver Neoplasms ; etiology ; genetics ; virology ; Male ; Middle Aged ; Polymorphism, Genetic

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers closely associated with chronic infection by the hepatitis B virus (HBV) or the hepatitis C virus (HCV) throughout the world. In this study, the genetic associations of 20 known polymorphisms in eight candidate genes, including angiotensinogen (AGT), cadherin 1 (CDH1), cyclooxygenase 2 (COX2), monocyte chemotactic protein-1 (MCP1), multidrug resistance 1 (MDR1), chemokine ligand 5 (RANTES), thrombospondin 2 (THBS2), and thrombospondin 4 (THBS4), were analyzed in a large chronic hepatitis B cohort (n=1,095) recruited from the Korean population. In addition, three polymorphisms in chemokine receptor 4 (CXCR4) and vimentin (VIM) identified in this study were also genotyped. Using logistic regression analysis controlling possible confounding factors, one common (freq.=0.367) promoter polymorphism of MCP1 (MCP1-2518G>A) among analyzed polymorphisms was significantly associated with clearance of HBV infection. The frequency of homozygotes for the MCP1-2518A allele (MCP1-2518A/A) among chronic hepatitis B virus (HBV) carrier patients was significantly higher than that among spontaneously recovered (SR) subjects (17.7% vs. 10.4%)(OR=1.78, P=0.004). Our findings imply a plausible explanation for the contribution of host genetic determinants to the variable outcome of HBV infection, which might provide valuable information for future genetic study in this area.
Promoter Regions (Genetics)/*genetics ; Polymorphism, Genetic/*genetics ; Middle Aged ; Male ; Humans ; Hepatitis B virus/*physiology ; Hepatitis B/complications/*genetics/therapy/*virology ; Haplotypes/genetics ; Female ; Chemokine CCL2/*genetics ; Carcinoma, Hepatocellular/epidemiology/etiology/genetics/virology ; Aged, 80 and over ; Aged ; Adult

BACKGROUND: The incidence and etiology of hepatocellular carcinoma (HCC) vary widely according to race and geographic regions. The insertional mutagenesis of adeno-associated virus 2 (AAV2) has recently been considered a new viral etiology of HCC. The aim of this study was to investigate the frequency and clinical characteristics of AAV2 in Korean patients with HCC. METHODS: A total of 289 unrelated Korean patients with HCC, including 159 Hepatitis-B-related cases, 16 Hepatitis-C-related cases, and 114 viral serology-negative cases, who underwent surgery at the Samsung Medical Center in Korea from 2009 to 2014 were enrolled in this study. The presence of AAV2 in fresh-frozen tumor tissues was investigated by DNA PCR and Sanger sequencing. The clinical and pathological characteristics of AAV2-associated HCC in these patients were compared with previous findings in French patients. RESULTS: The AAV2 detection rate in Korean patients (2/289) was very low compared with that in French patients (11/193). Similar to the French patients, the Korean patients with AAV2-related HCC showed no signs of liver cirrhosis. The Korean patients were younger than the French patients with the same AAV2-associated HCC; the ages at diagnosis of the two Korean patients were 47 and 39 yr, while the median age of the 11 French patients was 55 yr (range 43-90 yr). CONCLUSIONS: AAV2-associated HCC was very rare in Korean patients with HCC. Despite a limited number of cases, this study is the first to report the clinical characteristics of Korean patients with AAV2-associated HCC. These findings suggest epidemiologic differences in viral hepatocarcinogenesis between Korean and European patients.
Adult ; Asian Continental Ancestry Group ; Capsid Proteins/genetics ; Carcinoma, Hepatocellular/etiology/*pathology/virology ; DNA, Viral/chemistry/genetics/metabolism ; DNA-Binding Proteins/genetics ; Dependovirus/*genetics/isolation & purification/pathogenicity ; Female ; Humans ; Incidence ; Inverted Repeat Sequences/genetics ; Liver Neoplasms/etiology/*pathology/virology ; Male ; Middle Aged ; Parvoviridae Infections/complications/epidemiology ; Polymerase Chain Reaction ; Republic of Korea ; Sequence Analysis, DNA ; Viral Proteins/genetics

OBJECTIVETo identify the association strength of the prevalence of HBeAg, covalently closed circular DNA (cccDNA) and 1762/1764 nucleotide mutations of hepatitis B virus (HBV) with the occurrence of hepatocellular carcinoma (HCC) in Qidong high risk male cohort.

METHODSA cohort of 377 middle aged HBV infected men in Qidong was followed from January 1989 to December 2002. Incident HCC cases were carefully registered. A matched case-controlled study was conducted on 32 pairs of inherent HCC cases with their matched non-HCC controls. Serum HBeAg was measured by ELISA. cccDNA was detected by primer selected PCR. 1762/1764 nucleotide mutations of HBV was identified by PCR of X gene segment spanning the mutation region. Standard statistical comparison between the prevalence of each HBV marker in HCC versus in control group provided the odds ratio with P value to evaluate its association strength with HCC occurrence.

RESULTSSerum HBeAg prevalence was 53.1% (17/32) in HCC group versus and 15.6% (5/32) in controls (OR = 6.12, P < 0.01). Prevalence of serum cccDNA was detected in 62.5% (21/32) of HCC cases but in 25.0% (8/32) of controls (OR = 5.73, P < 0.01). Sequence of detected cccDNA was repeatedly found to be over 90% homologous with HBV. However, the mutation rate of nucleotide 1762/1764 was not found to be statistically higher in the HCC group versus its controls (OR = 1.54, P = 0.425).

CONCLUSIONSThe Qidong male case-controlled cohort had shown that serum HBeAg and cccDNA prevalence were tightly associated with hepatocellular carcinoma occurrence in HBV infected men. These biomarkers may have predictive value in earlier diagnosis and therapeutic effect monitoring.

Carcinoma, Hepatocellular ; etiology ; virology ; Case-Control Studies ; Cohort Studies ; DNA, Viral ; blood ; genetics ; Follow-Up Studies ; Hepatitis B e Antigens ; blood ; genetics ; Hepatitis B virus ; genetics ; Hepatitis B, Chronic ; complications ; virology ; Humans ; Liver Neoplasms ; etiology ; virology ; Male ; Middle Aged ; Point Mutation ; Prospective Studies ; Risk Factors

BACKGROUND/AIMS: Infection with hepatitis B virus (HBV) may result in various conditions. Natural course of HBV infection is influenced by various host immune factors and cytokines play a crucial role in host immune defense. This study was undertaken to investigate the association between HBV persistence and development of hepatocelluar carcinoma (HCC) and single nucleotide polymorphisms (SNPs) of interleukin (IL)-12A. METHODS: Between March 2002 and December 2004, seven hundred thirty Korean patients with HBV infection and 320 healthy individuals who recovered from HBV infection were enrolled. We assessed polymorphisms and haplotype in IL-12A, and the genotype distributions of the HBV clearance and persistence groups were compared in order to investigate the association between HBV persistence and SNPs of IL-12A. Moreover, the genotypic distributions between patients with HCC and without HCC were compared to investigate the association between the development of HCC and SNPs of IL-12A. RESULTS: We asssesed the SNPs of IL-12A at position +6400, +6624 and +7003. On the basis of logistic regression analysis, no statistically significant association with HBV persistence was observed with IL-12A exon 7 +6400, +6624, 3' UTR +7003 SNP and haplotype of IL-12A +6400/+6624/+7003. Furthermore, no statistically significant association of HCC development with IL-12A exon 7 +6400, +6624, 3' UTR +7003 SNP and haplotype of IL-12A +6400/+6624/+7003 was observed. CONCLUSIONS: These results suggest that SNPs and haplotype of IL-12A are not associated with HBV persistence and development of HCC. Further studies are needed to identify the host genetic factors in immune defense including cytokine gene polymorphisms of both IL-12A and IL-12B.
Adult ; Aged ; Carcinoma, Hepatocellular/etiology/*genetics/virology ; Female ; Genetic Predisposition to Disease ; Genotype ; Haplotypes ; Hepatitis B/complications/*genetics ; Hepatitis B virus/isolation & purification ; Hepatitis B, Chronic/complications/*genetics ; Heterozygote ; Humans ; Interleukin-12 Subunit p35/*genetics ; Liver Neoplasms/etiology/*genetics/virology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Retrospective Studies ; Risk Factors

OBJECTIVETo investigate the relationship of alcohol intake and hepatocellular carcinoma among patients with hepatitis B virus infection.

METHODSA total of 553 patients with HCC and 160 control subjects affected with hepatitis B virus were recruited. Serum virology, serum biochemistry, as well as demographic information were studied. Finally, risk factors were selected by stepwise Logistic regression analyse. Odds ratios (ORs) were estimated for each risk factor. According to alcohol intake, HCC patients were divided into three groups,then to observe the differences between them.

RESULTSElevated AST, GGT, ALP and AFP levels were seen more frequently in the HCC case groups compared to control group (P < 0.05). Multivariate analysis revealed that heavy alcohol use, smoking, positive family history of liver cancer is associated with HCC development among patients with hepatitis B virus infection. Significantly increased risk was found among patients for heavy alcohol use [A = 2.66 (2.01-3.50)] and for smoking [A = 2.51 (1.66-3.80)] and for positive family history of liver cancer [A = 1.64 (1.04-2.59)]. Compared to patients who did not have alcohol use, elevated GGT and ALP were seen more frequently in patients who had alcohol use either mild or heavy (P < 0.05).

CONCLUSIONSHeavy alcohol use, smoking, positive family history of liver cancer is positive correlation with HCC development among patients with hepatitis B virus infection in China. In patients with hepatitis B virus infection who also has history of heavy alcohol, the most risk factor of HCC is hepatitis B virus infection, not alcohol.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alcohol Drinking ; adverse effects ; Carcinoma, Hepatocellular ; epidemiology ; etiology ; virology ; Case-Control Studies ; China ; Female ; Hepatitis B ; complications ; virology ; Hepatitis B virus ; genetics ; isolation & purification ; physiology ; Humans ; Liver Neoplasms ; epidemiology ; etiology ; virology ; Male ; Middle Aged ; Risk Factors ; Young Adult

MicroRNA polymorphisms may be associated with carcinogenesis or immunopathogenesis of infection. We evaluated whether the mircoRNA-604 (miR-604) polymorphism can affect the persistence of hepatitis B virus (HBV) infection, and the development to hepatocellular carcinoma (HCC) in patients with chronic HBV infection. A total of 1,439 subjects, who have either past or present HBV infection, were enrolled and divided into four groups (spontaneous recovery, chronic HBV carrier without cirrhosis, liver cirrhosis and HCC). We genotyped the precursor miR-604 genome region polymorphism. The CC genotype of miR-604 rs2368392 was most frequently observed and T allele frequency was 0.326 in all study subjects. The HBV persistence after infection was higher in those subjects with miR-604 T allele (P=0.05 in a co-dominant and dominant model), which implied that the patients with miR-604 T allele may have a higher risk for HBV chronicity. In contrast, there was a higher rate of the miR-604 T allele in the chronic carrier without HCC patients, compared to those of the HCC patients (P=0.03 in a co-dominant model, P=0.02 in a recessive model). The T allele at miR-604 rs2368392 may be a risk allele for the chronicity of HBV infection, but may be a protective allele for the progression to HCC in chronic HBV carriers.
Adult ; Aged ; Aged, 80 and over ; Base Sequence ; Carcinoma, Hepatocellular/etiology/*genetics/pathology ; Case-Control Studies ; Demography ; Female ; Gene Frequency ; *Genetic Predisposition to Disease ; Genotype ; Hepatitis B Antibodies/blood ; Hepatitis B Surface Antigens/blood ; Hepatitis B e Antigens/blood ; Hepatitis B virus/metabolism ; Hepatitis B, Chronic/complications/*genetics/virology ; Humans ; Liver Neoplasms/etiology/*genetics/pathology ; Male ; MicroRNAs/*genetics/metabolism ; Middle Aged ; Polymorphism, Single Nucleotide ; Risk Factors

BACKGROUND/AIMS: Lamivudine (LAM) plus adefovir (ADV) combination therapy has been accepted as one of the best treatments for LAM-resistant chronic hepatitis B (CHB). The aim of this study was to determine the efficacy of this combination therapy in hepatocellular carcinoma (HCC) patients. METHODS: The medical records of CHB patients who developed LAM resistance and were treated with LAM plus ADV combination therapy for more than 6 months were reviewed. Their virological response (VR; undetectable HBV DNA) and biochemical response (BR; alanine aminotransferase normalization) were evaluated, and the findings of HCC and non-HCC patients were compared. RESULTS: The data from 104 patients (19 with HCC and 85 without HCC) were analyzed. The VR rates did not differ significantly between the HCC and non-HCC groups: 33.3% vs. 55.6% at 12 months (P=0.119), 58.3% vs. 67.2% at 24 months (P=0.742), 50% vs. 69.8% at 36 months (P=0.280), and 66.7% vs. 71.0% at 48 months (P=1.000). The BR rates also did not differ significantly between the groups: 55.6% vs. 84.0% at 12 months (P=0.021), 58.3% vs. 83.8% at 24 months (P=0.057), 70.0% vs. 77.8% at 36 months (P=0.687), and 66.7% vs. 80.6% at 48 months (P=0.591). CONCLUSIONS: The efficacy of LAM plus ADV combination therapy is comparable in HCC and non-HCC patients.
Adenine/*analogs & derivatives/therapeutic use ; Adult ; Antiviral Agents/*therapeutic use ; Carcinoma, Hepatocellular/*diagnosis/epidemiology/etiology ; DNA, Viral/analysis ; Drug Administration Schedule ; Drug Resistance, Viral ; Drug Therapy, Combination ; Genotype ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/*drug therapy/virology ; Humans ; Incidence ; Lamivudine/*therapeutic use ; Liver Cirrhosis/diagnosis/epidemiology/etiology ; Liver Neoplasms/*diagnosis/epidemiology/etiology ; Middle Aged ; Organophosphonates/*therapeutic use ; Retrospective Studies ; Treatment Outcome

BACKGROUND/AIMS: This study aimed to clarify the effect of obesity on the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving antiviral treatment. METHODS: This study applied a retrospective analysis to a historical cohort in Bundang Jesaeng Hospital. In total, 102 CHB patients were treated with entecavir as an initial treatment for CHB and checked for obesity using a body composition analyzer. Hepatic steatosis was measured semiquantitatively using Hamaguchi’s scoring system in ultrasonography. Risk factors for the development of HCC were analyzed, including obesity-related factors (body mass index [BMI], waist circumference [WC], waist-to-hip ratio [WHR], visceral fat area [VFA], and hepatic steatosis). RESULTS: The median follow-up duration of the patients was 45.2 months (interquartile range: 36.0-58.3 months). The cumulative incidence rates of HCC at 1 year, 3 years, and 5 years were 0%, 5.3%, and 9.0%, respectively. Univariable analysis revealed that the risk factors for HCC development were a platelet count of <120,000 /mm² (hazard ratio [HR]=5.21, P=0.031), HBeAg negativity (HR=5.61, P=0.039), and liver cirrhosis (HR=10.26, P=0.031). Multivariable analysis showed that the significant risk factor for HCC development was liver cirrhosis (HR=9.07, P=0.042). However, none of the obesity-related risk factors were significantly associated with HCC: BMI ≥25 kg/m² (HR=0.90, P=0.894), WC ≥90 cm (HR=1.10, P=0.912), WHR ≥0.9 (HR=1.94, P=0.386), VFA ≥100 cm² (HR=1.69, P=0.495), and hepatic steatosis (HR=0.57, P=0.602). CONCLUSION: HCC development is associated with liver cirrhosis but not obesity-related factors in CHB patients receiving entecavir.
Adult ; Antiviral Agents/*therapeutic use ; Body Mass Index ; Carcinoma, Hepatocellular/epidemiology/*etiology ; Cohort Studies ; DNA, Viral/blood ; Female ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B virus/genetics/isolation & purification ; Hepatitis B, Chronic/complications/*drug therapy/virology ; Humans ; Incidence ; Liver Cirrhosis/complications ; Liver Neoplasms/epidemiology/*etiology ; Male ; Middle Aged ; Obesity/*complications ; Proportional Hazards Models ; Retrospective Studies ; Risk Factors ; Viral Load