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Damage-specific DNA-binding protein 2 (DDB2) is a DNA repair protein mainly involved in nucleotide excision repair, which plays a pivotal role in maintaining genomic stability. In this study, we evaluated the association of single-nucleotide polymorphism (SNP) rs1050244 in miRNA target site of DDB2 gene with risk of hepatocellular carcinoma (HCC) among 1073 HCC patients and 1119 cancer-free controls in a southern Chinese population. Our results showed that no statistically significant association was found between DDB2 rs1050244 and HCC risk. In further analysis stratified by age, sex, smoking, alcohol drinking, and HBV infection status, we found that individuals carrying the CT/TT genotypes of SNP rs1050244 had a significantly decreased risk of HCC compared with those with the CC genotype among non-HBV infected population (adjusted OR = 0.31, 95% CI = 0.13–0.72), and a significant interaction was found between this SNP and HBV infection ( P interaction = 0.002). Our results suggested that the DDB2 rs1050244 C>T polymorphism was associated with the decreased risk of HCC among non-HBV infected population. Further studies with larger sample sizes are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Abstract Ferritin is not only a biomarker of total iron status and systemic inflammation but is also associated with metabolic disorders. A number of genetic variations have been identified to affect serum ferritin, but there is limited understanding of the genetic variations in serum ferritin. To evaluate the relationships among genetic variations, metabolism and ferritin, we performed a secondary analysis of our previous genome-wide association study of ferritin. After adjusting for population stratification and age, the rs671 in ALDH2 was significantly associated with ferritin concentrations (P -combined = 2.98 × 10−8). Men carrying the mutated genotype of rs671 had lower serum ferritin levels. BMI was the mediation between rs671 and ferritin (P = 0.003). Moreover, a significant interaction between rs671 and alcohol consumption on ferritin levels was observed (P = 3.02 × 10−4). rs671 genotypes were significantly relevant to serum ferritin in drinkers (P = 2.39 × 10−7). We reported that rs671 was associated with ferritin in a manner of BMI mediation. These findings will provide new insights into the impacts of genetic variations and metabolisms on serum ferritin levels. Highlights • rs671 is significantly associated with ferritin concentrations. • Men carrying the mutated genotype of rs671 have lower serum ferritin levels. • BMI is the mediation between rs671 and ferritin. • rs671 interacts with alcohol consumption in determining ferritin concentration. [ABSTRACT FROM AUTHOR]

Background Serum folate is important in clinical researches and DNA synthesis and methylation. Some loci and genes that are associated with folate levels had been detected by genome-wide association studies (GWAS), such as rs1801133 in MTHFR and rs1979277 in SHMT1 . Nevertheless, only a small part of variants has been clearly identified for serum folate. Hence, we conducted a GWAS to discover new inherited susceptibility and gene-environment interactions on serum folate concentration. Materials and methods In a healthy Chinese population of 1999 men, genotyping was performed using Illumina HumanOmni1-Quad BeadChip. Serum folate levels were measured by enzyme-linked immunosorbent assay (ELISA), pathway enrichment analysis and statistical analysis were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID) and Statistic Package for Social Science (SPSS). Results We validated that rs1801133 in MTHFR was significantly involved in serum folate ( P  = 4.21 × 10 −19 ). Surprisingly, we discovered three novel loci rs3782886, rs671, and rs4646776 of ALDH2 gene were suggestively significantly associated with folate serum folate levels in the male population studied ( P  = 2.17 × 10 −7 , P  = 3.60 × 10 −7 , P  = 3.99 × 10 −7 , respectively) after adjusting for population stratification, BMI and age. Men with the AA genotype had significantly higher serum folate levels compared with men with the GG/AG genotype. But we found ALDH2 gene mutation no relation to part of environmental factors on serum folate levels. Conclusion In a male Chinese population, genome-wide association study discovered that three novel SNPs rs3782886, rs671 and rs4646776 of ALDH2 gene were suggestively significantly associated with serum folate levels. [ABSTRACT FROM AUTHOR]

The H2A.Z variant histone 1 (H2AZ1) is aberrantly expressed in various tumors, correlating with an unfavorable prognosis. However, its role in hepatocellular carcinoma (HCC) remains unclear. We aimed to elucidate the pathways affected by H2AZ1 and identify promising therapeutic targets for HCC. Following bioinformatic analysis of gene expression and clinical data from The Cancer Genome Atlas and Gene Expression Omnibus database, we found 6,344 dysregulated genes related to H2AZ1 overexpression in HCC tissues (P < 0.05). We performed weighted gene co-expression network analysis to identify the gene module most related to H2AZ1. The H2AZ1-based index was further developed using Cox regression analysis, which revealed that the poor prognosis in the high H2AZ1-based index group could be attributed to elevated tumor stemness (P < 0.05). Moreover, the clinical model showed good prognostic potential (AUC > 0.7). We found that H2AZ1 knockdown led to reduced superoxide dismutase (SOD) activity, elevated malondialdehyde (MDA) levels, and increased apoptosis rate in tumor cells (P < 0.001). Thus, we developed an H2AZ1-based index model with the potential to predict the prognosis of patients with HCC. Our findings provide initial evidence that H2AZ1 overexpression plays a pivotal role in HCC initiation and progression.

Observational studies have reported associations between circulating biomarkers related to cardiovascular disease and the survival of patients with hepatocellular carcinoma. However, the relationship between these biomarkers and survival remains controversial. We conducted a two-sample Mendelian randomization analysis to investigate possible causal associations between cardiovascular disease biomarkers and hepatocellular carcinoma survival. Genetic risk scores, calculated using individual-level data from 866 cases of hepatitis B virus-related hepatocellular carcinoma in Guangxi, were utilized as proxies for four cardiovascular disease biomarkers: C-reactive protein, Apolipoprotein A-1, Cystatin C, and Lipoprotein(a). Associations between the genetic scores and survival were analyzed using Cox regression. The inverse-variance weighted method was used to estimate the summary statistics for the biomarkers and survival. Considering the multiple comparisons, the statistical significance was set at P < 0.0125. We observed a significant risk signal between genetically increased Cystatin C levels and poorer survival in hepatocellular carcinoma (HR for genetic scores = 1.29, 95% CI = 1.02-1.64; HR for inverse-variance weighted = 2.60, 95% CI = 1.45-4.65). Furthermore, we found a causal relationship of genetically determined Cystatin C and Lipoprotein(a) level with the survival of hepatocellular carcinoma patients with embolus. Our findings indicated the causal effects of increased levels of Cystatin C and Lipoprotein(a) on poorer survival in hepatocellular carcinoma., Competing Interests: None., (AJCR Copyright © 2023.)

Background: Super-enhancer (SE) refers to a regulatory element with super transcriptional activity, which can enrich transcription factors and drive gene expression. SE-related genes play an important role in the pathogenesis of malignant tumors, including hepatocellular carcinoma (HCC)., Methods: The SE-related genes were obtained from the human super-enhancer database (SEdb). Data from the transcriptome analysis and related clinical information with HCC were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) database. The upregulated SE-related genes from TCGA-LIHC were identified by the DESeq2R package. Multivariate Cox regression analysis was used to construct a four-gene prognostic signature. According to the median risk score, HCC patients were divided into high-risk and low-risk group patients., Results: The Kaplan-Meier (KM) curve showed that a significantly worse prognosis was found for the high-risk group ( P <0.001). In the TCGA-LIHC dataset, the area under the curve (AUC) values were 0.737, 0.662, and 0.667 for the model predicting overall survival (OS) over 1-, 3-, and 5- years, respectively, indicating the good prediction ability of our prediction model. This model's prognostic value was further validated in the LIRI-JP dataset and HCC samples (n=65). Furthermore, we found that higher infiltration level of M0 macrophages and upregulated of CTLA4 and PD1 in the high-risk group, implying that immunotherapy could be effective for those patients., Conclusion: These results provide further evidence that the unique SE-related gene model could accurately predict the prognosis of HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wei, Zhou, Long, Lin, Qiu, Chen, Huang, Qiu, Jiang, Wen, Liu, Li, Nong, Guo, Yu and Zhou.)

Background: Immunological-related genes (IRGs) play a critical role in the immune microenvironment of tumors. Our study aimed to develop an IRG-based survival prediction model for hepatocellular carcinoma (HCC) patients and to investigate the impact of IRGs on the immune microenvironment., Methods: Differentially expressed IRGs were obtained from The Genomic Data Commons Data Portal (TCGA) and the immunology database and analysis portal (ImmPort). The univariate Cox regression was used to identify the IRGs linked to overall survival (OS), and a Lasso-regularized Cox proportional hazard model was constructed. The International Cancer Genome Consortium (ICGC) database was used to verify the prediction model. ESTIMATE and CIBERSORT were used to estimate immune cell infiltration in the tumor immune microenvironment (TIME). RNA sequencing was performed on HCC tissue specimens to confirm mRNA expression., Results: A total of 401 differentially expressed IRGs were identified, and 63 IRGs were found related to OS on the 237 up-regulated IRGs by univariate Cox regression analyses. Finally, five IRGs were selected by the LASSO Cox model, including SPP1 , BIRC5 , STC2 , GLP1R , and RAET1E . This prognostic model demonstrated satisfactory predictive value in the ICGC dataset. The risk score was an independent predictive predictor for OS in HCC patients. Immune-related analysis showed that the immune infiltration level in the high-risk group was higher, suggesting that the 5-IRG signature may play an important role in mediating immune escape and immune resistance in the TIME of HCC. Finally, we confirmed the 5-IRG signature is highly expressed in 65 HCC patients with good predictive power., Conclusion: We established and verified a new prognosis model for HCC patients based on survival-related IRGs, and the signature could provide new insights into the prognosis of HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Long, Zhou, Wei, Lin, Qiu, Zhou, Chen, Jiang, Wen, Liu, Li, Zhou and Yu.)

Background: The NF-κB signaling pathway plays an important role in associating inflammation with tumor development and progression. However, few studies have reported that roles of genetic variants of the NF-κB signaling pathway genes in survival of patients with HBV-related hepatocellular carcinoma (HBV-HCC), especially with regards to potentially functional SNPs., Methods: We used multivariate Cox proportional hazards regression to evaluate associations between 2,060 single nucleotide polymorphisms (SNPs) in 20 NF-κB signaling pathway genes and survival of 866 HBV-HCC patients, which were randomly split (1:1) into discovery and validation datasets. Expression quantitative trait loci (eQTL) analysis was conducted to identify associations between survival-associated SNPs and mRNA expression of corresponding genes. Furthermore, online database was used to assess mRNA expression of corresponding genes and survival. Finally, receiver operating characteristic (ROC) curves were used to assess the prediction accuracy of models integrating both clinical and genetic variables on HCC survival., Results: A total of 6 SNPs in MAP3K14 remained significantly associated with OS of HBV-HCC patients ( P <0.05, BFDP<0.8). Further eQTL analysis demonstrated that significant correlations between the rs2074292 (G>A) A allele was associated with higher mRNA expression levels of MAP3K14 ( P =0.044) in normal liver tissue, which was associated with worse survival of HBV-HCC patients. In the additive model, after adjusting for age, sex, smoking status, drinking status, AFP level, cirrhosis, embolus and BCLC stage, the combined dataset showed that HBV-HCC patients carrying the rs2074292 AA and GA genotypes (HR=1.71, 95%CI= 1.29-2.27, P =0.000) (HR=1.40, 95%CI=1.10-1.77, P =0.005) have worse OS than GG genotype, respectively. The addition of risk genotypes to the prediction models increased the AUC significantly from 71.15% to 73.11% ( P =0.012) and from 72.55% to 74.21% ( P =0.010) for 1-year and 3-year OS, respectively., Conclusion: Our study indicated that MAP3K14 rs2074292 A allele may be a potential predictor of HBV-HCC survival, likely regulating MAP3K14 mRNA expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Liu, Qiu, Lin, Wei, Zhou, Liang, Li, Chen, Zhou and Yu.)

Objective: The effect of surgical margin (SM) on the postoperative prognosis of patients with solitary hepatocellular carcinoma (HCC) remains controversial. This study aimed to evaluate the effect of SM on the postoperative prognosis of patients with solitary HCC by using propensity score matching (PSM). Methods: Patients with solitary HCC who underwent liver resection were divided into a wide margin group (1.0 cm or more, group W) and a narrow margin group (< 1.0 cm, group N). Progression-free survival (PFS) and overall survival (OS) associated with the SM status and the factors influencing postoperative prognosis were evaluated. Results: Before PSM, the indicators were not balanced between the two groups. PFS and OS were significantly lower in group N than group W. The factors affecting postoperative prognosis were international normalized ratio (INR), AST, capsule integrity, microvascular invasion, tumour embolus and tumour size. After PSM, data of both groups were balanced and comparable, and no significant differences in OS or PFS between the two groups. The INR in the above affecting factors was excluded. Conclusion: For solitary HCC patients with negative SMs, SM size does not affect prognosis. INR, AST, capsule integrity, microvascular invasion, tumour embolus and tumour size are independent factors influencing the postoperative prognosis of solitary HCC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Management of prostate cancer, especially advanced prostate cancer, remains clinically challenging and requires the identification of new biomarkers and therapeutic targets that can be exploited to improve patient outcome. Galectin-3 (gal-3) is a carbohydrate-binding protein involved in cancer progression and metastasis, including prostate tissues. Gal-3 function is regulated by proteolytic cleavage and the cleaved gal-3 is implicated in tumor progression. This study is the first to determine gal-3 expressions with two monoclonal anti-gal-3 antibodies in prostate tissues to distinguish expression patterns between intact and cleaved gal-3 and analyze their clinical relevance. Our results showed gal-3 cleavage occurred in prostate cancer but not normal prostate. Gal-3 presented in tumor tissues was mainly the cleaved form that can be detected by the anti-gal-3 antibody targeting C terminal. The cleaved gal-3, but not the intact gal-3, was increased in prostate cancer compared to normal prostate tissues and positively associated with malignance, tumor progression and metastasis. In addition, the expression of cleaved gal-3 was closely related to PSA level, indicating a PSA-mediated degradation of intact gal-3 in prostate cancer. In summary, our findings suggested the cleaved gal-3 could be a valuable diagnostic biomarker and a therapeutic target for the treatment of prostate cancer, especially advanced metastatic prostate cancer., Competing Interests: None., (IJCEP Copyright © 2018.)