Per- and polyfluoroalkyl substances (PFASs) are widely used in numerous industrial processes and consumer products and are now ubiquitously distributed in the environment, thereby creating multiple routes of human exposure. Their physicochemical properties confer high persistence, bioaccumulation potential, and toxicity, which have raised increasing concern about their long-term impacts on human health. Because of its central role in xenobiotic uptake, metabolism, transport, and excretion, the liver is considered a major target organ of PFAS toxicity. Over the past few years, a growing body of epidemiological, in vivo, and in vitro evidence has linked PFAS exposure to a broad spectrum of hepatic abnormalities, including liver injury, cholestatic liver injury and bile acid dysregulation, metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). In addition to legacy long-chain PFASs, short-chain congeners and emerging alternatives such as GenX and 6:2 Cl-PFESA have also shown considerable hepatotoxic potential. This review summarizes current evidence on the contribution of PFAS exposure to liver disease, with particular attention to human relevance and the mechanisms underlying PFAS-induced hepatotoxicity, including oxidative stress, inflammatory activation, disruption of the gut-liver axis and enterohepatic circulation, lipid metabolic reprogramming, and impairment of bile acid homeostasis. Remaining knowledge gaps and future perspectives are also highlighted to support mechanistic understanding and improve PFAS-related liver risk assessment.

Arachidonic acid (AA) metabolism plays essential roles in inflammation, tissue regeneration, immune regulation, and tumorigenesis. However, the prognostic significance of genetic variants in AA metabolism genes for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. We analyzed 56 AA metabolism-related genes in 866 HBV-HCC patients using Cox proportional hazards regression, with Bayesian false discovery probability and false positive report probability for multiple testing correction. Two independent SNPs, CYP2A6 rs28399433 A > C (HR = 1.30, 95

JARID1B is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4). JARID1B has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unknown. Here we show that JARID1B is elevated in HCC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients. Overexpression of JARID1B in HCC cells increased proliferation, epithelial-mesenchymal transition, migration and invasion in vitro, and enhanced tumorigenic and metastatic capacities in vivo. In contrast, silencing JARID1B in aggressive and invasive HCC cells inhibited these processes. Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription. PTEN overexpression blocked JARID1B-driven proliferation, EMT, and metastasis. Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells. Targeting JARID1B may thus be a useful strategy to impede HCC cell invasion and metastasis.

Purpose: Nucleotide metabolism plays a critical role in cancer development, but the prognostic significance of genetic variants in nucleotide metabolism genes for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients remains unclear. Methods: We performed Cox proportional hazards regression analyses to evaluate the association between genetic variants in 94 nucleotide metabolism-related genes and overall survival (OS) in 866 HBV-HCC patients. To assess the potential biological relevance of the identified variants, the Bayesian false discovery probability and false-positive report probability were applied for multiple testing correction. Results: Two independent SNPs, DCTD rs17074255 G>A (HR = 1.22, 95% CI: 1.06-1.40, p = 0.005) and ENTPD2 rs3763662 G>A (HR = 1.18, 95% CI: 1.03-1.34, p = 0.015), were significantly associated with OS. A significant dose-dependent association between the number of risk genotypes and poorer OS was observed (Ptrend < 0.001). Luciferase reporter assays demonstrated allele-specific regulatory effects of rs3763662 on ENTPD2 expression (p < 0.001). DCTD and ENTPD2 mRNA expression levels were significantly elevated in HCC tumors in the UALCAN database and in our 103 paired samples. Higher expression levels of both genes were associated with poorer survival in the TCGA cohort (p = 0.003 and p < 0.001). Conclusions: Our findings suggest that ENTPD2 rs3763662 (supported by direct functional evidence) and DCTD rs17074255 (supported by eQTL and expression associations) may serve as potential prognostic indicators for HBV-HCC through the regulation of mRNA expression. These findings provide new insights into the role of nucleotide metabolism-related genetic variation in HBV-HCC progression and may facilitate prognostic assessment, pending replication in independent cohorts.

Purpose:Glycolysis is a group of metabolic processes that may alter tumor microenvironment to have effects on the growth and proliferation of tumor cells, including liver cancer. However, the effect of genetic variants in glycolysis pathway genes in survival of patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) remains unclear. Methods:We employed multivariable Cox proportional hazards regression analyses to estimate associations between genetic variants in 240 glycolysis pathway genes and overall survival (OS) of 866 patients with HBV-HCC, and we also used false positive report probability for multiple testing corrections. Results:We found that UGP2 rs4293553 G allele was significantly associated with a better OS of HBV-HCC patients [hazards ratio (HR) = 0.73, 95% confidence interval (CI) = 0.62-0.86, P < 0.001], and that FBP2 rs635087 G allele was significantly associated with a worse OS in these patients (HR = 1.38, 95% CI = 1.18-1.61, P < 0.001). The expression quantitative trait loci analysis using the GTEx database showed that the rs635087 G allele was significantly correlated with reduced FBP2 mRNA expression levels in normal liver tissues (P < 0.001), but such a correlation was not significant for the rs4293553 G allele. Functional annotation results indicate that these two single nucleotide polymorphisms have potential biological functions, providing biological plausibility for the observed associations. In addition, the mRNA expression levels of both UGP2 and FBP2 were significantly lower in HCC tissues than in normal liver tissues (both P < 0.001), and high expression levels of both UGP2 and FBP2 were significantly associated with favorable survival in HCC patients (both P < 0.001). Discussion:Our findings suggested that genetic variants in glycolysis pathway genes may serve as novel prognostic markers for survival of patients with HBV-HCC, especially FBP2 rs635087, if validated in additional larger studies and functional investigations.

Bicuspid aortic valve (BAV) represents a prevalent form of congenital heart disease. The NOTCH1 gene is implicated in the pathogenesis of BAV, and congenital valve anomalies caused by variants in this gene are classified as Aortic Valve Disease 1 (AOVD1), which is inherited in an autosomal dominant pattern. Echocardiographic data and peripheral blood samples were collected from a Chinese family manifesting a clinical phenotype characterized by various cardiovascular abnormalities, including BAV. Exome sequencing target enrichment technology was performed to identify candidate genes and variants. This was followed by family segregation analysis using Sanger sequencing. A novel nonsense variant, c.2266G > T (p.Glu756Ter), was identified in the NOTCH1 gene (NM_017617.5) within this family. Individuals harboring the p.Glu756Ter pathogenic variant (III4, II7, II9, and I2) exhibited BAV – associated phenotypes. Conversely, the proband carrying p.Glu756Ter pathogenic variant (IV1) presented with distinct clinical phenotypes, including a persistent left superior vena cava (PLSVC) and a widened coronary sinus. Family members without the p.Glu756Ter pathogenic variant showed no cardiovascular abnormalities. This variant is located in exon 14 of the NOTCH1 gene, resulting in a premature stop codon. Bioinformatics analysis predicted that p.Glu756Ter induces nonsense-mediated mRNA decay or produces a truncated protein, impairing NOTCH1 receptor function. The NOTCH1 variant is a prevalent genetic factor in BAV etiology, exhibiting both interfamilial and intrafamilial phenotypic variability with incomplete penetrance. PLSVC and a widened coronary sinus represent common anatomical variations within the general population. Nevertheless, the potential role of NOTCH1 variants in the development of these vascular anomalies should be considered.

Background and objectiveIn clinical practice, CK19 can be an important predictor for the prognosis of HCC. Due to the high incidence and mortality rates of HCC, more effective and practical prognostic prediction models need to be developed urgently.MethodsA total of 1,168 HCC patients, who underwent radical surgery at the Guangxi Medical University Cancer Hospital, between January 2014 and July 2019, were recruited, and their clinicopathological data were collected. Among the clinicopathological data, the optimal cutoff value of CK19-positive HCC was determined by calculating the area under the curve (AUC) using survival analysis and time-dependent receiver operating characteristic (timeROC) curve analysis. The predictors were screened using univariate and multivariate COX regression and least absolute shrinkage and selection operator (LASSO) regression to construct nomogram prediction models, and their predictive potentials were assessed using calibration curves and AUC values.ResultsThe 0% positive rate of CK19 was considered the optimal cutoff value to predict the poor prognosis of CK19-positive HCC. The survival analysis of 335 CK19-positive HCC showed no significant statistical differences in the overall survival (OS) and disease-free survival (DFS) of CK19-positive HCC patients. A five-factor risk (CK19, CA125, Edmondson, BMI, and tumor number) scoring model and an OS nomograph model were constructed and established, and the OS nomograph model showed a good predictive performance and was subsequently verified.ConclusionA 0% expression level of CK19 protein may be an optimal threshold for predicting the prognosis of CK19-positive HCC. Based on this, CK19 marker a good nomogram model was constructed to predict HCC prognosis.

Hereditary spastic paraplegia (HSP) is a rare and genetically heterogeneous neurodegenerative disorder, primarily defined by progressive lower-limb spasticity and weakness. Among the numerous genes implicated, pathogenic variants in the spastic paraplegia 7 (SPG7) gene represent one of the most common causes of HSP, whereas mutations in SCN4A, a skeletal muscle ion channel gene, are typically associated with a diverse spectrum of phenotypes, including hyperkalemic and hypokalemic periodic paralysis, potassium-aggravated myotonia, and congenital paramyotonia. To date, however, the coexistence of pathogenic variants in SPG7 and SCN4A within the same pedigree, and their potential pathogenic interplay, has not been documented. In this study, we performed comprehensive genetic profiling, including whole-exome sequencing, mitochondrial genome analysis, dynamic mutation screening, copy number variation assessment, and Sanger sequencing. We identified a novel heterozygous SPG7 variant (c.578A>G; p.E193G) alongside a known pathogenic SCN4A missense mutation (c.2111C>T; p.T704M). Remarkably, individuals harboring both variants presented with highly complex phenotypes that combined classical HSP manifestations with ion channel dysfunctions, such as congenital paramyotonia and hypokalemic periodic paralysis. These findings provide the first evidence of a possible genetic interaction between SPG7 and SCN4A, expanding the recognized clinical and molecular spectrum of HSP. Our results underscore the diagnostic value of multi-gene testing in patients with atypical or overlapping neuromuscular symptoms and highlight the importance of considering potential polygenic contributions when interpreting the clinical heterogeneity of HSP.

BackgroundDense deposit disease (DDD) is a rare renal disorder major affecting adolescents and children, characterized by an absence of distinctive clinical symptoms. Its coexistence with other renal conditions complicates both diagnosis and treatment in clinical practice.Case presentationWe described a 15-year-old male adolescent presenting with nephrotic syndrome as the initial manifestation, with urinalysis indicating significantly elevated protein and erythrocytes. Unexpectedly, the renal pathological biopsy of the patient exhibited strong positivity for both IgA and C3, characterized by petaloid deposition of C3 along glomerular capillary loops and the glomerular mesangial region, as well as linear deposition in Bowman's capsule and portions of the renal tubular basement membrane. Consequently, the patient was diagnosed with both DDD and IgA nephropathy. The presence of both in a single patient may result in more intricate pathogenic pathways.ConclusionsThis specific case elucidates the pathological characteristics of both diseases while investigating the intricate connections and lesion correlations that may occur between them, offering novel insights into their pathogenesis.

Liver cancer ranks sixth in cancer incidence and third in cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the primary histological subtype, and hepatitis B virus (HBV) carriers have a higher risk of HCC. Although several susceptibility loci for HCC have been identified in East Asian populations through genome-wide association studies (GWAS), the underlying biological mechanisms of this malignancy remain incompletely understood. Here, we conduct a two-stage GWAS including 2413 cases and 2794 HBV-positive controls from a high-incidence region in Southern China. The function of the susceptibility locus is investigated by bioinformatic and experimental approaches, supported by a xenograft model. We identify a 4p14 locus significantly associated with the risk of HCC (rs55718051, OR [95% CI] = 0.73 [0.67-0.80], Pmeta = 9.14 × 10-11), and 18q23 locus with borderline significance (rs12964643: OR [95% CI] = 0.75 [0.67-0.83], Pmeta = 1.11 × 10-7). Functional experiments indicate the role of rs55718051 in FAM114A1 expression regulation, possibly through the interaction with FOXA1. Knockdown of FAM114A1 significantly promote the oncogenic phenotypes in liver cancer cells, suggesting its potential tumor suppressor role. Our findings expand the understanding of HCC susceptibility and suggest FAM114A1 as a potential suppressor in HBV-related HCC carcinogenesis.

Amino acid metabolism (AAM) reprogramming plays a crucial role in hepatocellular carcinoma (HCC), but its genetic pathophysiology was not fully elucidated. Therefore, we employed a summary data-based Mendelian randomization (SMR) approach to identify putative causal effects of the AAM-related genes on hepatitis B virus (HBV)-HCC survival via integrating multi-omics data. Multivariate Cox proportional hazards regression models were used to evaluate associations between genetic variants of AAM-related genes and overall survival (OS) of HBV-HCC patients (n = 866). Next, we developed a pathway-specific genetic risk score (GRS) comprising variants in the AAM pathway. Subsequently, putative causal SNPs were prioritized using SMR by integrating HBV-HCC OS data with expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) from the blood, as well a eQTLs of liver tissues. We identified 23 independent variants associated with HBV-HCC OS, and the pathway-specific GRS derived from the identified variants was a significant predictor of HBV-HCC OS. The addition of the GRS significantly improved the predictive performance of the 5-year survival model (AUC increased from 72.04

Disulfidptosis is a novel form of programmed cell death involved in migration and invasion of cancer cells, but few studies investigated the roles of genetic variants in disulfidptosis-related genes in survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We used Cox proportional hazards regression analyses, Kaplan-Meier curves and receiver operating characteristic curves to assess effects of genetic variants in 14 disulfidptosis-related genes on overall survival of 866 HBV-HCC patients. The Bayesian false discovery probability was used for multiple testing corrections. We also investigated biological mechanisms of the significant variants through expression quantitative trait loci analyses using the data from publicly available databases, luciferase reporter assays and differential expression analyses. As a result, we identified two independently functional single nucleotide polymorphisms (SNPs) (INF2 rs4072285 G > A and INF2 rs4444271 A > T) that predicted overall survival of HBV-HCC patients, with adjusted hazard ratios of 1.60 (95% CI = 1.22-2.11, P = 0.001) and 1.50 (95% CI = 1.80-1.90, P < 0.001), respectively, after multiple testing correction. Luciferase reporter assays indicated that both INF2 rs4072285 A and INF2 rs4444271 T alleles increased INF2 mRNA expression levels (P < 0.001) that were also higher in HCC tumor tissues than in adjacent normal tissues (P < 0.001); such elevated INF2 expression levels were associated with a poorer survival of HBV-HCC patients (P < 0.001) in the TCGA database. In summary, this study supported that INF2 rs4072285 and INF2 rs4444271 may be novel biomarkers for survival of HBV-HCC patients.

Objective: The Chitinase 3-like protein 1 (CHI3L1) is currently used as a biomarker for the diagnosis of liver fibrosis. However, its prognostic value for hepatocellular carcinoma (HCC) patients remains controversial. In this study, we aimed to investigate the prognostic value of the CHI3L1 in HCC patients after hepatectomy. Methods: In total, 753 HCC patients who underwent curative hepatectomy between January 2017 to August 2021 were retrospectively recruited. The probability of overall survival (OS) was evaluated by the Kaplan-Meier method and compared between groups using the log-rank test. Cox proportional hazard regression analysis was used to determine the independent prognostic factors. A prognostic nomogram was constructed for further examine the clinical utility of CHI3L1 in HCC. Results: Kaplan-Meier analysis revealed that elevated serum CHI3L1 levels were associated with worse overall survival of HCC patients. Multivariate Cox regression analysis showed that the high-CHI3L1 group (>= 198.94 ng/ml) was associated with a shorter survival time compared with that in the low-CHI3L1 group (< 198.94 ng/ml) after adjustment for potential confounding factors (HR =1.43, 95% CI = 1.05-1.94, P = 0.024). Additionally, the nomogram had sufficient calibration and discriminatory power in the training cohort, with C-indexes of 0.723 (95% CI: 0.673-0.772). The validation cohort showed similar results. Finally, we demonstrated that the AUC of the nomogram was 0.752 (95% CI: 0.683-0.821), which had better predictive ability than AFP (AUC: 0.644, 95% CI: 0.577-0.711). Conclusion: Our results confirmed that the CHI3L1 could serve as an independent predictor for OS in HCC patients after hepatectomy. The nomogram showed a good performance in prognosis prediction of HCC.

Potentially modifiable risk factors for hepatocellular carcinoma (HCC) have been investigated in observational epidemiology studies in East Asian and European populations, whereas the causal associations of most of these risk factors remain unclear. We collected genome-wide association summary statistics of 22 modifiable risk factors in East Asians and 33 risk factors in Europeans. Genetic summary statistics of HCC were sourced from the Biobank Japan study (1,866 cases and 195,745 controls) for East Asians, and the deCODE genetics study (406 cases and 49,302 controls) and the UK Biobank (168 cases and 372 016 controls) for Europeans. Two-sample Mendelian randomization (MR) analyses were performed independently for East Asian and European populations. In East Asians, genetically predicted alcohol frequency, ever drinkers, aspartate aminotransferase (AST), hypothyroidism, chronic hepatitis B, and chronic hepatitis C, metabolic dysfunction-associated steatotic liver disease (MASLD), and autoimmune hepatitis were significantly associated with an increased HCC risk (P < 0.05/22). Among European population, alanine transaminase, AST, MASLD, percent liver fat, and liver iron content were significantly associated with a higher risk of HCC (P < 0.05/33). The replication dataset and meta-analysis further confirmed these results. Although East Asian and European populations have different factors for HCC, their common modifiable risk factors AST and MASLD for HCC, offer valuable insights for targeted intervention strategies to mitigate society burden of HCC.

The nod-like receptor protein 3 (NLRP3) is one of the most characterized inflammasomes involved in the pathogenesis of several cancers, including hepatocellular carcinoma (HCC). However, the effects of genetic variants in the NLRP3 inflammasome-related genes on survival of hepatitis B virus (HBV)-related HCC patients are unclear. We performed multivariable Cox proportional hazards regression analysis to evaluate associations between 299 single-nucleotide polymorphisms (SNPs) in 16 NLRP3 inflammasome-related genes and overall survival (OS) of 866 patients with HBV-related HCC. We further performed expression quantitative trait loci (eQTL) analysis using the data from the GTEx project and 1000 Genomes projects, and performed differential expression analysis using the TCGA dataset to explore possible molecular mechanisms underlying the observed associations. We found that two functional SNPs (PANX1 rs3020013 A > G and APP rs9976425 C > T) were significantly associated with HBV-related HCC OS with the adjusted hazard ratio (HR) of 0.83 [95

Nucleotide excision repair (NER) is an important DNA damage repair pathway involved in prognosis of cancer. The aim of this study was to investigate the association between genetic variants in NER pathway genes and overall survival (OS) of hepatocellular carcinoma (HCC) patients. Cox proportional hazards regression analyses was performed to investigate the associations between single nucleotide polymorphism (SNPs) in candidate genes and OS of 866 patients with operable hepatitis B virus (HBV) related HCC. The relationship between SNPs and corresponding genes was estimated by GTEx database and 1000 Genomes project. Online biological information databases were used for functional annotation of SNPs. Gene expression was calculated using data obtained from The Cancer Genome Atlas (TCGA). Kaplan-Meier plotter was used to evaluate the relationship between gene expression and OS in HBV-HCC patients. cBioPortal database was applied to observe the mutation rate of genes in HCC tumor tissues. We identified two independent functional SNPs were significantly associated with OS of HBV-HCC patients [ USP45 rs4840048 T > C: Hazard ratio (HR) = 0.64, 95% confidence interval (CI) = 0.48–0.86, P = 0.003) and PRPF19 rs7116665 C > A: HR = 1.31, 95%CI = 1.13–1.53, P < 0.001). Besides, rs4840048 T allele was significantly correlated with higher USP45 mRNA expression levels ( P = 0.010), while rs7116665 A allele was significantly correlated with decreased PRPF19 mRNA expression levels ( P = 0.003). In the TCGA database, high expression of USP45 and PRPF19 was associated with poorer survival in HCC patients ( P = 0.026 and P < 0.001, respectively). Our finding indicated that the two SNPs in NER pathway genes may be novel biomarkers of the survival in HBV-HCC patients.

BackgroundAlthough the sphingolipid metabolism pathway is known to play a significant role in tumor progression, there have been few studies on how genetic variants in the sphingolipid metabolism pathway genes affect the survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).MethodsWe utilized available genotyping data to conduct multivariate Cox proportional hazards regression model analysis, examining the associations of 12,188 single nucleotide polymorphisms (SNPs) in 86 sphingolipid metabolism pathway genes on the survival of 866 HBV-HCC patients, and the model was also used in additive interaction analysis. We used bioinformatics functional prediction and expression quantitative trait locus (eQTL) analysis to explore the potential functions of SNPs and to evaluate the association of SNPs with the corresponding mRNA expression, respectively. We also used the online database TIMER2.0 (http://timer.comp-genomics.org/) to analyze the relationship between the corresponding mRNA expression levels and immune cell infiltration.ResultsOur study found that GBA2 rs1570247 G>A was significantly associated with elevated survival of HBV-HCC patients [(hazards ratio (HR)=0.74, 95% confidence interval (CI)=0.64-0.86, P<0.001)]. And on an additive scale, a synergistic effect was observed between the GG genotype of rs1570247 and advanced BCLC stage. Among HBV-HCC patients with advanced BCLC stage, those carrying the GBA2 rs1570247 GG genotype exhibited a significantly elevated risk of mortality (HR=3.32, 95%CI=2.45-4.50). Further functional prediction and eQTL analysis revealed that rs1570247 were located in the 5’ untranslated region of the GBA2, the A allele of SNP rs1570247 was associated with higher mRNA expression levels of GBA2 in normal liver tissues (P=0.009). Moreover, we observed a positive correlation between GBA2 mRNA expression and the infiltration level of B lymphocytes cell (R=0.331, P<0.001), while a negative correlation was noted between GBA2 mRNA expression and the infiltration level of macrophage M2 in HCC (R=-0.383, P<0.001).ConclusionOur findings suggest that GBA2 rs1570247 G>A in sphingolipid metabolism pathway may be a key factor for survival of HBV-HCC patients by regulating the expression of corresponding genes and affecting the infiltration level of immune cells.

Purpose:P53 is a suppressor gene closely related to carcinogenesis. However, the associations between genetic variants in the p53 signaling pathway and prognosis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unknown. The current study aims to analyze associations between the single nucleotide polymorphisms (SNPs) in p53 pathway-related genes and survival of patients with HBV-HCC. Methods:We evaluated the associations between 4698 SNPs in 70 genes of the p53 pathway and overall survival (OS) of 866 patients in additive genetic models by using Cox proportional hazards regression analysis. Stepwise multivariable Cox regression analysis was conducted to determine the independent effects of identified SNPs in single-locus analyses. The expression of quantitative trait loci (eQTL) was also analyzed using data from GTEx and 1000 Genomes Project, and functional prediction of SNPs was performed by using RegulomeDB v2.2, 3DSNP v2.0, HaploReg v4.2 and VannoPortal. Results:We found that two novel SNPs of CD82 rs7925603 A > G and PMAIP1 rs4396625 A > T, were significantly and independently associated with OS [adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were 1.27 (1.10-1.48) and 0.77 (0.66-0.91), respectively; P = 0.001 and = 0.002, respectively] and that the combined risk genotypes of these SNPs showed a significant association with OS in patients with HBV-HCC (P trend < 0.001). Further eQTL analysis in the GTEx dataset showed that the rs7925603 G allele was associated with lower CD82 mRNA expression levels, while the rs4396625 T allele was associated with higher PMAIP1 mRNA expression levels in whole blood cells. Conclusion:We identified two observed survival-associated SNPs in CD82 and PMAIP1 in the p53 pathway, which influenced HBV-HCC survival possibly through a mechanism of altering mRNA expression. Large studies are warranted to validate our findings.

This study profiled global single cell-spatial-bulk transcriptome landscapes of hepatocellular carcinoma (HCC) ecosystem from six HCC cases and a non-carcinoma liver control donor. We discovered that intratumoral heterogeneity mainly derived from HCC cells diversity and pervaded the genome-transcriptome-proteome-metabolome network. HCC cells are the core driving force of taming tumor-associated macrophages (TAMs) with pro-tumorigenic phenotypes for favor its dominant growth. Remarkably, M1-types TAMs had been characterized by disturbance of metabolism, poor antigen-presentation and immune-killing abilities. Besides, we found simultaneous cirrhotic and HCC lesions in an individual patient shared common origin and displayed parallel clone evolution via driving disparate immune reprograms for better environmental adaptation. Moreover, endothelial cells exhibited phenotypically conserved but executed differential functions in a space-dependent manner. Further, the spatiotemporal traits of rapid recurrence niche genes were identified and validated by immunohistochemistry. Our data unravels the great significance of HCC cells in shaping vibrant tumor ecosystems corresponding to clinical scenarios.

AbstractBackgroundAlthough the Notch pathway plays an important role in formation and progression of hepatocellular carcinoma (HCC), few studies have reported the associations between functional genetic variants and the survival of hepatitis B virus (HBV)‐related HCC.MethodsIn the present study, we performed multivariable Cox proportional hazard regression analysis to evaluate associations between 36,101 SNPs in 264 Notch pathway‐related genes and overall survival (OS) of 866 patients with HBV‐related HCC.ResultsIt was found that three independent SNPs (NEURL1B rs4868192, CNTN1 rs444927 and FCER2 rs1990975) were significantly associated with the HBV‐related HCC OS. The number of protective genotypes (NPGs) were significantly associated with better survival in a dose‐response manner (ptrend <0.001). Compared with the model with sole clinical factors, the addition of protective genotypes to the predict models significantly increased the AUC, i.e., from 72.72% to 75.13% (p = 0.002) and from 72.04% to 74.76 (p = 0.004) for 3‐year and 5‐year OS, respectively. The expression quantitative trait loci (eQTL) analysis further revealed that the rs4868192 C allele was associated with lower mRNA expression levels of NEURL1B in the whole blood (p = 1.71 × 10‐3), while the rs1990975 T allele was correlated with higher mRNA expression levels of FCER2 in the whole blood and normal liver tissues (p = 3.51 × 10−5 and 0.033, respectively).ConclusionsThree potentially functional SNPs of NEURL1B, CNTN1 and FCER2 may serve as potential prognostic biomarkers for HBV‐related HCC.