Increased Hepatocellular Carcinoma Susceptibility Research Articles

Contribution of PNPLA3 gene polymorphisms to hepatocellular carcinoma susceptibility in the Chinese Han population

ObjectivesThe purpose of this study was to investigate the association of PNPLA3 single nucleotide polymorphisms (SNPs) (rs738409 C > G, rs3747207 G > A, rs4823173 G > A, and rs2896019 T > G) with hepatocellular carcinoma (HCC) susceptibility.MethodsThis case–control study included 484 HCC patients and 487 controls. Logistic regression analysis was performed to study the associations of PNPLA3 gene polymorphisms with HCC susceptibility, and odds ratios with their corresponding 95% confidence intervals were calculated to evaluate these correlations.ResultsIn the overall analysis, we found that the G allele (OR = 1.25, 95% CI = 1.04–1.50, p = 0.018, false discovery rate (FDR)-p = 0.035) and GG genotype (OR = 1.59, 95% CI = 1.06–2.39, p = 0.024, FDR-p = 0.048) of rs2896019 were significantly associated with increased HCC susceptibility. In stratified analysis, we found that all four SNPs were related to increased HCC susceptibility in subjects aged > 55 years. In haplotype analysis, the GAAG haplotype was significantly associated with increased HCC susceptibility (OR = 1.25, 95% CI = 1.03–1.53, p = 0.023, FDR-p = 0.046). Besides, we noticed that rs738409 was significantly correlated with alpha-fetoprotein (AFP) (p = 0.007), and HCC patients with the GG genotype had a higher level of AFP.ConclusionsOur study suggested that PNPLA3-rs2896019 was significantly associated with an increased susceptibility to HCC.

Two BRM promoter polymorphisms predict poor survival in patients with hepatocellular carcinoma

Polymorphisms in the promoter of the BRM gene, a critical subunit of the chromatin remodeling SWI/SNF complex, have previously been implicated in risk and prognosis in Caucasian-predominant lung, head and neck, esophageal, and pancreatic cancers, and in hepatocellular cancers in Asians. We investigated the role of these polymorphisms in hepatocellular carcinoma (HCC) risk and prognosis. HCC cases were recruited in a comprehensive cancer center while the matched controls were recruited from family practice units from the same catchment area. For risk analyses, unconditional logistic regression analyses were performed in HCC patients and matched healthy controls. Overall survival analyses were performed using Cox proportional hazard models, Kaplan-Meier curves, and log-rank tests. In 266 HCC cases and 536 controls, no association between either BRM promoter polymorphism (BRM-741 or BRM-1321) and risk of HCC was identified (P > 0.10 for all comparisons). There was significant worsening of overall survival as the number of variant alleles increased: BRM-741 per variant allele adjusted hazards ratio (aHR) 5.77, 95% confidence interval (CI) 2.89-11.54 and BRM-1321 per variant allele aHR 4.09, 95%CI 2.22-7.51. The effects of these two polymorphisms were at least additive, where individuals who were double homozygotes for the variant alleles had a 45-fold increase in risk of death when compared to those who were double wild-type for the two polymorphisms. Two BRM promoter polymorphisms were strongly associated with HCC prognosis but were not associated with increased HCC susceptibility. The association was strongest in double homozygotes for the allele variants.

Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls.

BackgroundConflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D) of human HFE (hereditary hemochromatosis) gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma (HCC).MethodsAn updated systematic review and meta-analysis was conducted to evaluate the potential role of HFE polymorphisms in the susceptibility to NAFLD, liver cirrhosis and HCC. After retrieving articles from online databases, eligible studies were enrolled according to the selection criteria. Stata/SE 12.0 software was utilized to perform the statistical analysis.ResultsIn total, 43 articles with 5,758 cases and 14,741 controls were selected. Compared with the control group, a significantly increased risk of NAFLD was observed for the C282Y polymorphism in the Caucasian population under all genetic models and for the H63D polymorphism under the allele, heterozygote and dominant models (all OR>1, Passociation<0.05). However, no significant difference between liver cirrhosis cases and the control group was observed for HFE C282Y and H63D (all Passociation>0.05). In addition, we found that HFE C282Y was statistically associated with increased HCC susceptibility in the overall population, while H63D increased the odds of developing non-cirrhotic HCC in the African population (all OR>1, Passociation<0.05). Moreover, a positive association between compound heterozygosity for C282Y/H63D and the risk of NAFLD and HCC, but not liver cirrhosis, was observed.ConclusionOur meta-analysis provides evidence that the HFE C282Y and H63D polymorphisms confer increased genetic susceptibility to NAFLD and HCC but not liver cirrhosis. Additional well-powered studies are required to confirm our conclusion.

Association between transforming growth factor-β1 -509 C&gt;T variants and hepatocellular carcinoma susceptibility: a meta-analysis

The transcriptional activity of transforming growth factor-β (TGF-β) is increased in subjects with hepatocellular carcinoma (HCC). Recent studies have indicated that the -509C genotype in hepatitis B virus (HBV)-infected subjects and the -509T genotype in hepatitis C virus (HCV)-infected subjects can increase the transcriptional activity of the TGF-β1 gene. We conducted a meta-analysis to clarify whether these two hepatitis viruses affect the association between TGF-β1 C-509T variants and HCC susceptibility. Using data derived from 8 case-control studies available in the PubMed database (5 with Asian and 3 with Caucasian populations), including 1,427 cases and 3,735 controls [1,610 patients with chronic liver disease and 2,125 healthy controls], we calculated pooled odds ratios with corresponding 95% confidence intervals. We used dominant (TT + CT vs. CC), recessive (TT vs. CC + CT), and co-dominant (TT vs. CC and CT vs. CC) genetic models. An overall analysis showed no association between the TGF-β1 C-509T variants and HCC susceptibility for all models. In contrast, a subgroup analysis, based on the infecting hepatitis viruses, provided the following results. Among the cases and controls with chronic liver disease, the TGF-β1 C-509T variants were significantly associated with decreased HCC susceptibility for two models with HBV-infected subjects, whereas the variants were significantly associated with increased HCC susceptibility for one model with HCV-infected subjects. Among the cases and healthy controls, there was a significant association between the TGF-β1 C-509T variants and increased HCC susceptibility for two models involving HCV-infected subjects. Among the cases and the entire control group, the same results were obtained for all genetic models with HCV-infected subjects. Although further data accumulation is required, our results suggest that these two hepatitis viruses affect the association between TGF-β1 C-509T variants and HCC susceptibility in opposite manners.

Association Between XPD Lys751Gln and Asp312Asn Polymorphisms and Hepatocellular Carcinoma Risk

Genetic polymorphisms of xeroderma pigmentosum group D (XPD) in the nucleotide excision repair pathway may influence cancer susceptibility by affecting the capacity for DNA repair. Studies investigating the association between XPD Lys751Gln and Asp312Asn polymorphisms and hepatocellular carcinoma (HCC) risk reported inconsistent results. The aim of this study was to quantitatively summarize the evidence for such an association.Eligible studies were identified by searching electronic databases including PubMed, Embase, Cochrane library, and CBM, Chinese Biomedical Literature Database, for the period up to October 2014. The association of XPD Lys751Gln and Asp312Asn polymorphisms and HCC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).Finally, a total of 11 studies with 4322 cases and 4970 controls were included for XPD Lys751Gln polymorphism and 6 studies with 2223 cases and 2441 controls were available for XPD Asp312Asn polymorphism. With respect to XPD Lys751Gln polymorphism, statistically significant increased HCC risk was found when all studies were pooled into the meta-analysis (Gln/Gln vs Lys/Lys: OR = 1.363, 95% CI 1.065–1.744, P = 0.014; Lys/Gln vs Lys/Lys: OR = 1.205, 95% CI 1.099–1.321, P = 0.000; Gln/Gln+Lys/Gln vs Lys/Lys: OR = 1.300, 95% CI 1.141–1.480, P = 0.000). In subgroup analyses by ethnicity, source of control, Hardy–Weinberg equilibrium (HWE) in controls, hepatitis B virus (HBV) infection, and statistically significant increase of HCC risk was found in East Asians, population-based studies, studies consistent with HWE, and HBV-positive subjects, but not in mixed/other populations, hospital-based studies, studies deviating from HWE, and HBV-negative subjects. With respect to XPD Asp312Asn polymorphism, no significant association with HCC risk was found in the overall and subgroup analyses.The results suggest that the XPD Lys751Gln polymorphism contributes to increased HCC susceptibility, especially in East Asian populations. Further, large and well-designed studies are required to validate this association.

The association of common functional polymorphisms in mir-146a and mir-196a2 and hepatocellular carcinoma risk: evidence from a meta-analysis.

MicroRNAs (miRNAs) are small non-coding RNA molecules that function as tumor suppressors or oncogenes. Single nucleotide polymorphisms (SNPs) located in the miRNAs influence the function of mature miRNAs and may contribute to cancer development. Studies investigating the association between miR-146a rs2910164 and miR-196a2 rs11614913 polymorphisms and hepatocellular carcinoma (HCC) risk reported inconsistent results. We performed a meta-analysis of all available studies to summarize this situation.Eligible studies were identified by search of electronic databases including PubMed, Embase, and Cochrane library for the period up to August 2014. The association of miR-146a rs2910164 and miR-196a2 rs11614913 polymorphisms and HCC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).Finally, a total of 12 studies with 4171 cases and 4901 controls were included for miR-146a rs2910164 polymorphism and 10 studies with 4687 cases and 4990 controls were available for miR-196a2 rs11614913 polymorphism. With respect to miR-146a rs2910164 polymorphism, statistical significant increased HCC risk was found when all studies were pooled into the meta-analysis (GG+CG vs CC: OR = 1.097, 95% CI 1.005–1.197, P = 0.037). In subgroup analyses by ethnicity, source of control, and HWE in controls, significant increase of HCC risk was found in Asians, population-based studies, and studies consistent with HWE, but not in Caucasians, hospital-based studies, and studies inconsistent with HWE. With respect to miR-196a2 rs11614913 polymorphism, no significant association with HCC risk was found in the overall and subgroup analyses.The results suggest that the miR-146a rs2910164 polymorphism contributes to increased HCC susceptibility, especially in Asian populations. Further large and well-designed studies are required to validate this association.

Association between a single nucleotide polymorphism of the XRCC1 gene and hepatocellular carcinoma susceptibility in the Chinese Han population

The human X-ray repair cross-complementing protein 1 (XRCC1) gene is a potentially gene determining hepatocellular carcinoma (HCC) susceptibility. The purpose of this study was to evaluate the association between XRCC1 and susceptibility to HCC. The association of XRCC1 polymorphisms with HCC susceptibility was investigated in 460 HCC patients and 463 controls using the created restriction site-polymerase chain reaction method. Our results indicate that the c.1471G>A variant could be detected and that the allele and genotype frequencies were statistically different between cases and controls. The AA genotype was strongly associated with increased HCC susceptibility as compared with the GG wild genotype (OR = 2.214, 95%CI = 1.493-3.283, χ(2) = 15.97, P < 0.0001). In addition, significantly increased HCC susceptibility was also found in a dominant and recessive model (P < 0.01). The allele A could contribute to HCC susceptibility compared with the G allele (OR = 1.480, 95%CI = 1.224-1.789, χ(2) = 16.44, P = 0.0001). Results from this study indicate that the XRCC1 c.1471G>A polymorphism is associated with HCC susceptibility in the Chinese Han population. Future studies on larger populations are essential to confirm this association.

Insertion/Deletion Polymorphisms in the Promoter Region of BRM Contribute to Risk of Hepatocellular Carcinoma in Chinese Populations

BackgroundBRM (Brahma homologue) is well known for its critical role in tumor suppression and cancer development. Genetic variations in the promoter region of BRM have been suggested to be associated with loss of BRM expression and lung cancer risk. To the authors’ knowledge, no study on the role of BRM genetic polymorphisms in hepatocellular carcinoma (HCC) risk has been performed.Methodology/Principal FindingsIn two independent case-control studies containing 796 HCC cases and 806 cancer-free individuals, we genotyped two putative functional insertion/deletion (indel) polymorphisms [BRM-1321 (rs3832613) and BRM-741 (rs34480940)] within promoter region of BRM in Chinese populations using a PCR-based method. Real-time RT-PCR analysis was used to explore the genotype-phenotype correlation between these polymorphisms and BRM expression in both tissue samples and HCC cell lines. Logistic regression analysis showed that compared to BRM-1321del/del genotype, the ins/del and ins/ins variant genotypes had an increased HCC risk [adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.19–1.82; adjusted OR = 2.55, 95% CI = 1.75–3.72, respectively]. No significant association between BRM-741 and HCC incidence was observed. However, stratification analysis revealed a significant association between ins/ins genotype of BRM-741 and increased HCC susceptibility in smokers (adjusted OR = 2.07, 95% CI = 1.33–3.22). Quantitative PCR analyses demonstrated that the genotypes of BRM-1321 and the corresponding haplotypes were significantly correlated with BRM expression in vivo. Compared with ins/ins genotype, subjects carrying ins/del and del/del genotype had 2.30 and 4.99 fold higher BRM expression in HCC tissue samples, respectively. Similar trends were observed in western blot analysis at protein level.Conclusions/SignificanceOur findings suggest that BRM promoter polymorphism (BRM-1321) could regulate BRM expression and may serve as a potential marker for genetic susceptibility to HCC.

Association of CYP1A2 genetic polymorphisms with hepatocellular carcinoma susceptibility: a case–control study in a high-risk region of China

Aflatoxin B1 exposure is one of the major risk factors for hepatocellular carcinoma (HCC). CYP1A2 is a cytochrome P450 isoenzyme that plays an important role in the bioactivation of AFB1 to its carcinogenic metabolite. The study was designed to assess whether genetic polymorphisms in CYP1A2 are associated with HCC susceptibility in a high-risk region. A case-control study of 431 HCC cases and 550 cancer-free controls recruited from an HCC endemic region in China was carried out. Three single nucleotide polymorphisms, namely -3860G > A (CYP1A2*1C), -3113G > A, and 5347T > C (CYP1A2*1B) were genotyped by polymerase chain reaction-restriction fragment length polymorphism methods. Homozygous carriers of the major haplotype -3860G/-3113G/5347C were associated with increased HCC susceptibility in the overall population (odds ratio [OR] = 1.65, 95% confidence interval [CI]: 1.11-2.46, P = 0.014), in HBsAg seronegative individuals (OR = 2.69, 95% CI: 1.43-5.06, P = 0.002), and in heavy smokers (OR = 2.14, 95% CI: 1.21-3.80, P=0.009). In addition, individuals carrying at least one CYP1A2*1C allele showed significantly decreased HCC risk (OR = 0.49, 95% CI: Q0.27-0.86, P = 0.013) in the HBsAg seronegative subpopulation. Furthermore, as compared with HBsAg seropositive patients, wild-type homozygotes of the CYP1A2*1C polymorphism were significantly over-represented in HBsAg seronegative patients (P = 0.024). No significant association between CYP1A2 genetic polymorphisms and HCC risk was observed in either HBsAg seropositive individuals or non-smokers. CYP1A2 genetic polymorphisms are associated with HCC susceptibility in smokers and HBsAg seronegative individuals in the Fusui endemic region.