Hepatocellular Carcinoma Susceptibility 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.

Research Progress on the Correlation between Acetaldehyde Dehydrogenase 2 and Hepatocellular Carcinoma Development.

Hepatocellular carcinoma (HCC) is the predominant pathologic type of primary liver cancer. It is a malignant tumor of liver epithelial cells. There are many ways to treat HCC, but the survival rate for HCC patients remains low. Therefore, understanding the underlying mechanisms by which HCC occurs and develops is critical to explore new therapeutic targets. Aldehyde dehydrogenase 2 (ALDH2) is an important player in the redox reaction of ethanol with endogenous aldehyde products released by lipid peroxidation. Increasing evidence suggests that ALDH2 is a crucial regulator of human tumor development, including HCC. Therefore, clarifying the relationship between ALDH2 and HCC is helpful for formulating rational treatment strategies. This review highlights the regulatory roles of ALDH2 in the development of HCC, elucidates the multiple potential mechanisms by which ALDH2 regulates the development of HCC, and summarizes the progress of research on ALDH2 gene polymorphisms and HCC susceptibility. Meanwhile, we envision viable strategies for targeting ALDH2 in the treatment of HCC SIGNIFICANCE STATEMENT: Numerous studies have aimed to explore novel therapeutic targets for HCC, and ALDH2 has been reported to be a critical regulator of HCC progression. This review discusses the functions, molecular mechanisms, and clinical significance of ALDH2 in the development of HCC and examines the prospects of ALDH2-based therapy for HCC.

The Influence of ESR2 Gene Polymorphisms on Susceptibility to Hepatitis B Virus-Related Chronic Hepatitis, Liver Cirrhosis, and Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) represents an estrogen-dependent tumor. The action of estrogen is regulated via estrogen receptor (ER). Polymorphisms in ERα gene, ESR1, are known to be related to HCC susceptibility among people carrying chronic hepatitis B (CHB). But the effect of ERβ on HCC is still largely unclear, and studies about the genetic variability of ESR2 and HCC are rare. For understanding ESR2's effect on HCC, this work tested two polymorphisms in the ESR2 gene promoter as well as the associations with CHB, HCC, and hepatitis B virus (HBV)-related liver cirrhosis (LC) among the Guangxi population. This work enrolled a total of 137 CHB, 136 LC, and 149 HBV-related HCC patients, together with 146 normal subjects. ESR2 polymorphisms rs3020449 and rs2978381 were examined using the SNaPshot genotyping technique. The AG genotype and dominant model of rs3020449 were related to the decreased CHB susceptibility. In both the overall and subgroup analyses, no associations were observed with the remaining models in all patient groups (those with CHB, HBV-related LC, and HCC), but associations were found between the dominant (TC+CC vs TT) and allele models (C vs T) of rs2978381 and increased HBV-related LC and HCC susceptibility, but not CHB. These findings suggest that rs3020449 polymorphism of ESR2 gene makes great contribution to the decreased CHB risk and that rs2978381 significantly contributed to higher risks of HBV-related LC and HCC.

Genome-wide functional integration identified MAZ-controlled RPS14 dysregulation in hepatocellular carcinoma.

Chronic infection with Hepatitis B virus (HBV) significantly increases the risk of hepatocellular carcinoma (HCC), particularly in Eastern Asia. However, only a subset of individuals with chronic HBV infection develop HCC, suggesting the role for genetic factors in HCC etiology. Despite genome-wide association studies (GWASs) identifying multiple single nucleotide polymorphisms (SNPs) associated with HBV-related HCC susceptibility, the underlying mechanisms and causal genetic polymorphisms remain largely unclear. To address this, we developed The Updated Integrative Functional Genomics Approach (TUIFGA), an methodology that combines data from transcription factor (TF) cistromics, ATAC-seq, DNAase-seq, and the 1000 Genomes Project to identify cancer susceptibility SNPs within TF-binding sites across human genome. Using TUIFGA, we discovered SNP rs13170300 which located in the TF MAZ binding motif of RPS14. The RPS14 rs13170300 was significantly associated with HCC risk in two case-control sets, with the T allele as the protective allele (Shandong discovery set: TT OR = 0.60, 95% CI = 0.49-0.74, P = 1.0 × 10-6; CT OR = 0.69, 95% CI = 0.55-0.86, P = 0.001; Jiangsu validation set: TT OR = 0.70, 95% CI = 0.56-0.87, P = 0.001; CT OR = 0.65, 95% CI = 0.53-0.82, P = 1.6 × 10-4). SNP rs13170300 affected MAZ binding in the RPS14 promoter, resulting in allele-specific changes in gene expression. RPS14 functions as a novel oncogene in HCC, specifically via activating the AKT signaling. Our findings present important insights into the functional genetics underlying HBV-related HCC development and may contribute to personalized approaches for cancer prevention and novel therapeutics.

Evaluation of doxorubicin administrations in hepatocellular carcinoma in terms of genetic polymorphism, case study: Egypt

PurposeThis scientific article aims to evaluate the efficacy of the drug Doxorubicin for treating hepatocellular carcinoma (HCC) in Egypt. The study analyzes data from patients referred to a multi-disciplinary consultation at the National Cancer Institute, Cairo University. The study includes 40 intermediate-stage HCC patients who underwent treatment with either Doxorubicin-Lipiodol or Doxorubicin-loaded drug-eluting beads-trans-arterial chemoembolization (DEB-TACE).Design/methodology/approachPatients referred to a multi-disciplinary consultation at the National Cancer Institute, Cairo University with a possible diagnosis of HCC in the intermediate stage were eligible for the study.FindingsThe study finds that the plasma peak concentration of Doxorubicin is significantly higher in patients treated with Lipiodol compared to those treated with DEB-TACE. The median plasma peak concentration of patients treated with Lipiodol was significantly higher 424 (202.5–731) than the peak level of patients treated with beads 84.95 (26.6–156.5) with p-value = 0.036. However, there is no significant difference in other pharmacokinetic parameters between the two treatment groups. The research article also investigates the genetic polymorphisms in HCC patients treated with Doxorubicin-Lipiodol and Doxorubicin-loaded DEB-TACE. It identifies a significant association between the ABCB1 gene (C3435T) and the concentration of Doxorubicin in plasma. Patients with the CCand computed tomography (CT) genotypes of ABCB1 have higher concentrations of Doxorubicin compared to those with the TT genotype. Furthermore, the study examines the progression-free survival rates and tumour response in the two treatment groups. It demonstrates that DEB-TACE patients have a higher progression-free survival rate compared to cTACE patients. DEB-TACE also leads to better tumour regression.Originality/valueThe current study helps to increase the understanding of the genetic factors that may contribute to HCC susceptibility in the Egyptian population. However, it is essential to consider that genetic polymorphism is just one aspect of HCC risk, and other factors such as environment, lifestyle and viral infections also play crucial roles. Further research is needed to elucidate the complex interactions between genetic and environmental factors in HCC development among Egyptians.

Association of MBOAT7 rs641738 polymorphism with hepatocellular carcinoma susceptibility: A systematic review and meta-analysis.

The MBOAT7 rs641738 single-nucleotide polymorphism (SNP) has been proven to influence various liver diseases, but its association with hepatocellular carcinoma (HCC) susceptibility has been debated. To address this discrepancy, we conducted the current systematic review and meta-analysis. To perform a systematic review and meta-analysis on association of MBOAT7 SNP and HCC susceptibility. We performed a systematic review in PubMed, Web of Science, Scopus, and EMBASE; applied specific inclusion and exclusion criteria; and extracted the data. Meta-analysis was conducted with the meta package in R. Sensitivity and subgroup analyses were also performed. This meta-analysis was registered in PROSPERO (CRD42023458046). Eight studies were included in the systematic review, and 12 cohorts from 6 studies were included in the meta-analysis. Our meta-analysis revealed an association between the MBOAT7 SNP and HCC susceptibility in both the dominant [odds ratio (OR): 1.14, 95% confidence interval (95%CI): 1.02-1.26, P = 0.020] and recessive (OR: 1.21, 95%CI: 1.05-1.39, P = 0.008) models. Subgroup analysis revealed that stratification of the included patients by geographical origin showed a significant association in Asia (OR: 1.20, 95%CI: 1.03-1.39). This meta-analysis underscores the contribution of the MBOAT7 rs641738 SNP to hepatocarcinogenesis, especially in Asian populations, which warrants further investigation.

Vitamin D receptor rs3782905 and vitamin D binding protein rs7041 polymorphisms are associated with hepatocellular carcinoma susceptibility in cirrhotic HCV patients

BackgroundThe severity of chronic hepatitis C and susceptibility to hepatocellular carcinoma (HCC) are associated with genetic variations within vitamin D receptor (VDR) in several populations. This study aims to determine the significance of the VDRs (rs2228570, rs3782905, rs11568820) and DBP (rs7041) for the susceptibility to HCC in Egyptian patients with chronic HCV infection and their effect on the progression of liver cirrhosis to carcinogenesis.MethodsSingle nucleotide polymorphisms (SNPs) VDR (rs2228570, rs3782905), and DBP rs7041 were genotyped using restriction fragment length-PCR (RFLP-PCR) technique and VDR rs11568820 was genotyped using single strand polymorphism PCR (SSP PCR). These SNPs genotypes, haplotypes and linkage disequilibrium analyses were examined in 299 Egyptian individuals (100 HCV-cirrhotic patients, 99 HCC- HCV patients, and 100 healthy controls).ResultThe VDR rs2228570 CC genotype, VDR rs3782905 GC and CC genotypes, and DBP rs7041 GG genotype are significantly higher in HCC. It is noteworthy that, VDR rs3782905 CC and DBP rs7041 TG genotypes are higher in HCV induced liver cirrhosis than with HCC progression in HCV infected patients. Furthermore, among patients, the relationship between these SNPs and smoking status, gender, and HCC susceptibility was reported.ConclusionAmong the four investigated SNPs, there are associations between VDR rs3782905 and DBP rs7041 and the HCC progression in Egyptian patients chronically infected with HCV. These SNPs are considered as risk factors in HCV induced liver cirrhosis and HCC. The combinations of these SNPs with smoking status and gender are statistically linked to a high risk of HCC. Future research with a larger sample size of subjects with HCV infection is advised, because chronic liver disease induced by HCV infection is the primary cause of HCC in Egypt. We recommend screening of these SNPs for prediction of LC and HCC development in HCV infected patients, which may improve the used therapeutic protocol. These results suggest that VDR polymorphisms may be potential determinants for HCC susceptibility in Egyptian HCV patients.

Olaparib enhances radiation-induced systemic anti-tumor effects via activating STING-chemokine signaling in hepatocellular carcinoma

Although Poly (ADP-ribose) polymerase (PARP) inhibitors have been clinically approved for cancers with BRCA mutations and are known to augment radiotherapy responses, their roles in promoting the abscopal effect and mediating immunotherapy in BRCA-proficient hepatocellular carcinoma (HCC) remain underexplored. Our study elucidates that olaparib enhances the radio-sensitivity of HCC cells. Coadministration of olaparib and irradiation induces significant DNA damage by generating double-strand breaks (DSBs), as revealed both in vitro and in immune-deficient mice. These DSBs activate the cGAS-STING pathway, initiating immunogenic cell death in abscopal tumors. STING activation reprograms the immune microenvironment in the abscopal tumors, triggering the release of type I interferon and chemokines, including CXCL9, CXCL10, CXCL11, and CCL5. This in turn amplifies T cell priming against tumor neoantigens, leading to an influx of activated, neoantigen-specific CD8+ T-cells within the abscopal tumors. Furthermore, olaparib attenuated the immune exhaustion induced by radiation and enhances the responsiveness of HCC to immune checkpoint inhibitors. Collectively, our data advocate that a synergistic regimen of PARP inhibitors and radiotherapy can strategically reinforce both local (primary) and systemic (abscopal) tumor control, bolstering HCC susceptibility to immunotherapy.

Suppressor of Cytokine Signaling-3 Gene Polymorphisms and the Risk of Hepatocellular Carcinoma in Chronic Hepatitis C Patients in Egypt.

Hepatocellular carcinoma (HCC) contributes significantly to cancer mortalities worldwide. The association between a specific single nucleotide polymorphism (SNP) located within the SOCS3 gene as well as the likelihood of hepatocellular carcinoma (HCC) progression in individuals with chronic hepatitis C virus (CHC) was found to be significant. We aimed to study SOCS3 gene polymorphisms at rs4969168 and rs4969170and HCC susceptibility in individuals with CHC. The current prospective study involved 111 subjects divided in to three groups (HCC, HCV with and with no cirrhosis, and apparently healthy individuals). Tumor staging was done using BCLC staging system. SOCS3 (rs4969168 and rs4969170) gene polymorphisms' analysis was done utilizing real-time polymerase chain reaction (RT-PCR) (via DNA extracted from all subjects). All subjects underwent a complete history, medical examination, and laboratory and radiological data collection. Compared to healthy controls, homozygous AA genotypes and heterozygous GA genotypes were substantially overrepresented in HCC patients as well as those with CHCaccompanied by cirrhosis.AFP, smoking, glucose level, and AA genotype of rs4969170 might be critical significant parameters for HCC development. SOCS3 gene polymorphisms at rs4969168 and rs4969170 are associated with HCC and liver fibrosis progression in the Egyptian population with CHC infection.

Polyphyllin I attenuates the invasion and metastasis via downregulating GRP78 in drug-resistant hepatocellular carcinoma cells.

Drug resistance to chemotherapy agents presents a major obstacle to the effective treatment of hepatocellular carcinoma (HCC), a common type of liver cancer. Increasing evidence indicates a link between drug resistance and the recurrence of HCC. Polyphyllin I (PPI), a promising pharmaceutical candidate, has shown potential therapeutic advantages in the treatment of sorafenib-resistant hepatocellular carcinoma (SR-HCC cells). In this study, we sought to investigate the mechanism underlying the inhibitory effect of PPI on the invasion and metastasis of SR-HCC cells. Our in vitro studies included scratch wound-healing migration assays and transwell assays to examine PPI's effect on HCC cell migration and invasion. Flow cytometry was employed to analyze the accumulation or efflux of chemotherapy drugs. The results of these experiments demonstrated that PPI increased the susceptibility of HCC to sorafenib while inhibiting SR-HCC cell growth, migration, and invasion. Molecular docking analysis revealed that PPI exhibited a higher binding affinity with GRP78. Western blot analysis and immunofluorescence experiments showed that PPI reduced the expression of GRP78, E-cadherin, N-cadherin, Vimentin, and ABCG2 in SR-HCC cells. Interference with and overproduction of GRP78 in vitro impacted the proliferation, migration, invasion, and metastasis of HCC cells. Further examination revealed that PPI hindered the expression of GRP78 protein, resulting in a suppressive effect on SR-HCC cell migration and invasion. Histological examination of tumor tissue substantiated that administering PPI via gavage to HepG2/S xenograft nude mice inhibited tumor growth and significantly reduced tumor size, as evidenced by xenograft experiments involving nude mice. Hematoxylin and eosin (HE) staining of tumor tissue specimens, along with immunohistochemistry (IHC), were conducted to evaluate the expression levels of Ki67, GRP78, N-cadherin, Vimentin, and ABCG2. The results indicated that PPI administration decreased the levels of proteins associated with metastasis and markers of drug resistance in tumor tissues, impeding tumor growth and spread. Overall, our findings demonstrated that PPI effectively suppressed the viability, proliferation, invasion, and metastasis of SR-HCC cells both in vitro and in vivo by modulating GRP78 activity. These findings provide new insights into the mechanism of PPI inhibition of SR-HCC cell invasion and metastasis, highlighting PPI as a potential treatment option for sorafenib-resistant HCC.

Association of TERT (rs2736098 and rs2736100) genetic variants with elevated risk of hepatocellular carcinoma: a retrospective case–control study

Hepatocellular carcinoma (HCC) is an inflammatory problematic issue with higher mortality among different ethnic populations. The telomerase reverse transcriptase (TERT) gene has an imperative role in the proliferation of various cancerous illnesses, particularly HCC. Moreover, the TERT (rs2736098 and rs2739100) variants were correlated with the HCC susceptibility and telomere shortening, but with unconvincing outcomes. The main purpose of this outward work is to assess the correlation between these significant variants within the TERT gene and the elevated risk of HCC with the aid of various computational bioinformatics tools. This study included 233 participants [125 cancer-free controls and 108 HCC patients] from the same locality. In addition, 81.5% of HCC patients were positive for HCV autoantibodies, while 73.1% of HCC patients were positive for cirrhotic liver. Genomic DNA of the TERT (rs2736098 and rs2736100) variants were characterized utilizing the PCR–RFLP method. Interestingly, the frequencies of TERT (rs2736098*A allele) and TERT (rs2736100*T allele) conferred a significant correlation with increased risk of HCC compared to healthy controls (p-value = 0.002, and 0.016, respectively). The TERT (rs2736098*A/A) genotype indicated a definite association with positive smoking and splenomegaly (p-value < 0.05), while the TERT (rs2736100*T/T) genotype observed a significant difference with higher levels of HCV autoantibodies (p-value = 0.009). In conclusion, this significant work confirmed the contribution of the TERT (rs2736098*A and rs2736100*T) alleles with elevated risk of HCC progression and telomere shortening among Egyptian subjects.

Outer dynein arm docking complex subunit 2 polymorphism rs7893462 modulates hepatocellular carcinoma susceptibility and can serve as an overall survival biomarker for hepatitis B virus-related hepatocellular carcinoma after hepatectomy: a cohort study with a long-term follow-up

BackgroundGenetic variants of outer dynein arm docking complex subunit 2 (ODAD2) have been reported to be closely associated with primary ciliary dyskinesia and colorectal cancer in previous studies, but the association of genetic variants of ODAD2 with hepatocellular carcinoma (HCC) has not been reported.MethodsWe enrolled 80 healthy subjects and 468 Guangxi hepatitis B virus (HBV)-related HCC patients in this study. A case–control study method was used to explore the association of different ODAD2-rs7893462 genotypes with hepatocarcinogenesis. A comprehensive survival analysis was used to explore the association of rs7893462 with the prognosis of HBV-related HCC in Guangxi.ResultsThrough a case–control study, we observed that patients carrying the G allele of rs7893462 had a markedly increased susceptibility to hepatocarcinogenesis (odds ratio = 1.712, 95% confidence interval = 1.032–2.839, P = 0.037). We found that there were significant prognosis differences among three different genotypes of rs7893462. Nomogram analysis suggested that the contribution of rs7893462 polymorphisms to the prognosis of HBV-related HCC was second only to the BCLC stage. Stratified survival analysis suggested that the AG genotype of rs7893462 was an independent prognostic risk factor for HBV-related HCC. Joint effect survival analysis also observed that the AG genotype of rs7893462 combined with clinical parameters could significantly identify HBV-related HCC patients with different prognostic outcomes more accurately, and the AG genotype was also observed to be independent of clinical factors in HBV-related HCC survival.ConclusionThe ODAD2-rs7893462 polymorphisms can be used as an independent prognostic indicator of HBV-related HCC overall survival and are significantly associated with susceptibility to hepatocarcinogenesis.

Association of hypoxia-inducible factor 1α expression with susceptibility to hepatitis B virus-related hepatocellular carcinoma: A meta-analysis.

Hypoxia-inducible factor 1α (HIF-1α) triggers tumorigenesis and progression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Inconsistent findings have been reported on the influence of HIF-1α over-expression on the clinical outcomes of HBV-related HCC. This study aims to clarify the role of HIF-1α overexpression in the tumorigenesis and prognosis of HBV-induced HCC. Systematic and comprehensive search of online papers was carried out to elucidate the contribution of HIF-1α expression to susceptibility of HBV-induced HCC. STATA 12.0 software was utilized to analyze available data extracted from all eligible literature. Publication bias and sensitivity were comprehensively analyzed. A total of 23 published studies involving 2244 subjects were finally screened. The HIF-1α expression was remarkably upregulated in HBV-induced HCC tissues than in normal liver tissues, non-tumorous tissues, paraneoplastic tissues, and non-HBV HCC tissues. The high HIF-1α expression tended to be positively related to capsular infiltration (odds ratio (OR) 1.767; 95% confidence interval (CI) 1.058, 2.950). The HIF-1α expression was relevant to lymph node metastasis (OR 3.778; 95% CI 1.666, 8.568). High levels of HIF-1α expression tended to be closely implicated in portal vein invasion (OR 6.728, 95% CI 2.191, 20.656) but were irrelevant to alpha-fetoprotein, cirrhosis, Edmondson grading, tumor size, age, gender, and histological grade. Analysis of pooled data showed that HIF-1α was not statistically relevant to poor overall survival in HBV-related HCC. Our data provides compelling evidence that HIF-1α overexpression may imply a greater probability of invasion and metastasis in patients with HBV-induced HCC.

Construction of a diagnostic model for hepatitis B-related hepatocellular carcinoma using machine learning and artificial neural networks and revealing the correlation by immunoassay

HBV infection profoundly escalates hepatocellular carcinoma (HCC) susceptibility, responsible for a majority of HCC cases. HBV-driven immune-mediated hepatocyte impairment significantly fuels HCC progression. Regrettably, inconspicuous early HCC symptoms often culminate in belated diagnoses. Nevertheless, surgically treated early-stage HCC patients relish augmented five-year survival rates. In contrast, advanced HCC exhibits feeble responses to conventional interventions like radiotherapy, chemotherapy, and surgery, leading to diminished survival rates. This investigation endeavors to unearth diagnostic hallmark genes for HBV-HCC leveraging a bioinformatics framework, thus refining early HBV-HCC detection. Candidate genes were sieved via differential analysis and Weighted Gene Co-Expression Network Analysis (WGCNA). Employing three distinct machine learning algorithms unearthed three feature genes (HHIP, CXCL14, and CDHR2). Melding these genes yielded an innovative Artificial Neural Network (ANN) diagnostic blueprint, portending to alleviate patient encumbrance and elevate life quality. Immunoassay scrutiny unveiled accentuated immune damage in HBV-HCC patients relative to solitary HCC. Through consensus clustering, HBV-HCC was stratified into two subtypes (C1 and C2), the latter potentially indicating milder immune impairment. The diagnostic model grounded in these feature genes showcased robust and transferrable prognostic potentialities, introducing a novel outlook for early HBV-HCC diagnosis. This exhaustive immunological odyssey stands poised to expedite immunotherapeutic curatives' emergence for HBV-HCC.

The rs72613567:TA polymorphism in HSD17B13 is associated with survival benefit after development of hepatocellular carcinoma.

The influence of genetic factors on survival following a diagnosis of hepatocellular carcinoma (HCC) remains unclear. To assess whether genetic polymorphisms influencing the susceptibility to develop HCC are also associated with HCC prognosis. We included United Kingdom Biobank (UKB) participants diagnosed with HCC after study enrolment. The primary outcome was all-cause mortality. Patients were followed from the date of HCC diagnosis to death or the registry completion date. Five HCC susceptibility loci were investigated: rs738409 (PNPLA3), rs58542926 (TM6SF2); rs72613567 (HSD17B13); rs2242652 (TERT) and rs708113 (WNT3A). The associations between these genetic variants and HCC mortality risk were assessed using Cox regression, adjusted for age, sex, ethnicity, aetiology, severity of the underlying liver disease and receipt of curative HCC treatment. The final sample included 439 patients; 74% had either non-alcoholic fatty liver disease or alcohol-related liver disease. There were 321 deaths during a mean follow-up of 1.9 years per participant. Kaplan-Meier survival estimates at 1, 3 and 5 years were 53.2%, 31.2% and 22.6% respectively. In multivariate analysis, rs72613567:TA (HSD17B13) was the only genetic susceptibility variant significantly associated with all-cause mortality risk (aHR: 0.74; 95% CI: 0.61-0.90; p = 0.003). Other associated factors were Baveno stage 3-4 (aHR: 1.65; 95% CI: 1.05-2.59; p = 0.03) and HCC treatment with curative intent (aHR: 0.25; 95% CI: 0.17-0.37; p < 0.001). The rs72613567:TA polymorphism in HSD17B13 is not only associated with a reduction in the risk of developing HCC but with a survival benefit in HCC once established. Therapeutic inhibition of HSD17B13 may augment survival in individuals with HCC.

Genetic profile of MIF single nucleotide polymorphism (rs755622 G>C) in hepatocellular carcinoma among Egyptian patients.

To evaluate the role of MIF gene polymorphism rs755622 G>C in occurrence and progression of hepatocellular carcinoma (HCC) among a cohort of Egyptian patients. This case-control study was conducted on 50 patients with HCC after chronic viral hepatitis and 50 healthy volunteers, recruited between July 2021 and January 2022. All patients with HCC were evaluated for severity of liver disease using a Child-Pugh score, and TNM and BCLC scoring systems. MIF 173 G>C (rs755622) single nucleotide polymorphism was performed for all participants by polymerase chain reaction using restriction fragment length polymorphism technique (RFLP-PCR). Overall results showed significantly higher frequencies of GG (wild homozygous genotype) and mutant heterozygous genotype GC and G allele (OR = 6.303, 95% CI: 3.374-11.775) among patients with HCC compared to the control group (p = 0.001) for all. Also, significantly higher frequency of genotype GG was detected among patients with advanced Child scores (B and C) (p = 0.039) and TNM stages (III and IV) (p = 0.013). There was significantly higher frequency of the G allele among patients with multiple hepatic focal lesions compared to those with a single focal lesion (p = 0.01). An obvious role of MIF (rs755622) gene polymorphism could have an important role in susceptibility and progression of HCC among patients with chronic viral hepatitis induced liver cirrhosis.

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.

The Contribution of Matrix Metalloproteinase-7 Promoter Genotypes to Hepatocellular Carcinoma Susceptibility.

Metalloproteinase-7 (MMP-7) has been previously found to be up-regulated in hepatocellular carcinoma (HCC) specimens and cells, favoring epithelial-mesenchymal transition. However, the contribution of MMP-7 genotypes to HCC has not been revealed to date. The study aimed to evaluate the contribution of MMP-7 promoter A-181G (rs11568818) and C-153T (rs11568819) genotypes on the risk of HCC in Taiwan, where HCC incidence is extremely high compared to worldwide data. In this case-control study, MMP-7 genotypes and their association with cigarette smoking and alcohol drinking habits were determined in 298 HCC patients and 889 healthy subjects by a typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Ever smokers and alcohol drinkers were represented with higher percentages in the case group compared to the control group. MMP-7 rs11568818 genotypes were not found differentially distributed in case and control groups (p for trend=0.5246). People of the analyzed cohort of the present study were all of CC genotypes at their rs11568819 polymorphic sites, without any CT or TT genotypes. As for gene-lifestyle interactions, people with variant genotypes at MMP-7 rs11568818 had the same odds for HCC development compared to the wild-type AA genotype, no matter whether the subjects belonged to the smoker, non-smoker alcohol drinker, or non-drinker groups. MMP-7 variant genotypes did not present any significance towards being a marker for HCC risk in Taiwanese.

Genetic Polymorphisms of lncRNA LINC00673 as Predictors of Hepatocellular Carcinoma Progression in an Elderly Population.

Long noncoding (lnc)RNAs are reported to be key regulators of tumor progression, including hepatocellular carcinoma (HCC). The lncRNA long intergenic noncoding RNA 00673 (LINC00673) was indicated to play an important role in HCC progression, but the impacts of genetic variants (single-nucleotide polymorphisms, SNPs) of LINC00673 on HCC remain unclear. A TaqMan allelic discrimination assay was performed to analyze the genotypes of three tagging SNPs, viz., rs9914618 G &gt; A, rs6501551 A &gt; G, and rs11655237 C &gt; T, of LINC00673 in 783 HCC patients and 1197 healthy subjects. Associations of functional SNPs of LINC00673 with HCC susceptibility and clinicopathologic variables were analyzed by logistic regression models. After stratification by confounding factor, we observed that elderly patients (≥60 years) with the LINC00673 rs9914618 A allele had an increased risk of developing HCC under a codominant model (p = 0.025) and dominant model (p = 0.047). Moreover, elderly patients carrying the GA + AA genotype of rs9914618 exhibited a higher risk of having lymph node metastasis compared to those who were homozygous for the major allele (p = 0.013). Genotype screening of rs9914618 in HCC cell lines showed that cells carrying the AA genotype expressed higher LINC00673 levels compared to the cells carrying the GG genotype. Further analyses of clinical datasets from the Cancer Genome Atlas (TCGA) showed that LINC00673 expressions were upregulated in HCC tissues compared to normal tissues, and were correlated with advanced clinical stages and poorer prognoses. In conclusions, our results suggested that the LINC00673 rs9914618 polymorphism may be a promising HCC biomarker, especially in elderly populations.

Association between the risk of hepatitis virus-related hepatocellular carcinoma and EGF polymorphism: A PRISMA-compliant updated meta-analysis.

Background:The study aims to provide a comprehensive account of the association between the epidermal growth factor (EGF) + 61A/G polymorphism (rs4444903) and susceptibility to virus-related hepatocellular carcinoma (HCC).Methods:Electronic searching of the Chinese National Knowledge Infrastructure, Wanfang, Chinese Scientific Journal Database (VIP), PubMed, Web of Science, and Embase was conducted to select eligible studies. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated to assess the strength of the association.Results:In this study, a total of 18 articles were included with 2692 cases and 5835 controls for assessing the association between rs4444903 and HCC risk. The pooled results showed that the EGF + 61A/G polymorphism was significantly associated with the risk of virus-related HCC in all genetic models. Stratified analyses were conducted based on ethnicity, study quality, source of controls, type of controls, number of cases and genotyping method. The results showed that EGF + 61A/G polymorphisms significantly affect HCC susceptibility in different stratified populations. High heterogeneity was observed across included studies, and meta-regression analysis demonstrated that race, type of controls, and study quality contribute to the observed heterogeneity.Conclusion:This pooled analysis found that EGF + 61A/G polymorphism was significantly associated with the risk of HCC.