• Hepatocellular carcinoma
• Liver tumour
• Mutations
• Patients
• Tumor protein gene

• Humans
• Male
• Female
• Liver Neoplasms/genetics
• Liver Neoplasms/epidemiology
• Nigeria/epidemiology
• Adult
• Risk Factors
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/epidemiology
• Middle Aged
• Genetic Predisposition to Disease
• Gene Frequency
• Tumor Suppressor Protein p53/genetics
• Case-Control Studies
• Genotype
• Polymorphism, Genetic

• HCC
• Prognosis
• Recurrence
• TERT promoter mutation
• TP53 mutation

• Humans
• Telomerase/genetics
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/mortality
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/mortality
• Male
• Tumor Suppressor Protein p53/genetics
• Female
• Biomarkers, Tumor/genetics
• Mutation
• Middle Aged
• Prognosis
• Neoplasm Recurrence, Local/genetics
• Neoplasm Recurrence, Local/pathology
• Aged
• Adult
• Promoter Regions, Genetic/genetics

• 82372331 National Natural Science Foundation of China
• 2023NSFC0716 Project of Science and Technology Department of Sichuan Province

• Cancer
• Telomere shortening
• Telomeres

• ZYYCXTD-C-202205 the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine
• CI2021B009 the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences
• HLCMHPP2023085 the High Level Chinese Medical Hospital Promotion Project
• HLCMHPP202308506 the High Level Chinese Medical Hospital Promotion Project
• HLCMHPP2023005 the High Level Chinese Medical Hospital Promotion Project
• 81774294 the National Natural Science Foundation of China
• 82104961 the National Natural Science Foundation of China
• ZZ14-YQ-016 the Fundamental Research Funds for the Central public welfare research institutes
• ZZ13-YQ-028 the Fundamental Research Funds for the Central public welfare research institutes
• CI2021A01816 CACMS Innovation Fund
• CI2021A01814 CACMS Innovation Fund
• CI2021A01805 CACMS Innovation Fund

• cancer screening
• cancer epigenetics

• Humans
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/diagnosis
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• DNA Methylation
• alpha-Fetoproteins/genetics
• Cell-Free Nucleic Acids/genetics
• Biomarkers, Tumor/genetics

• K08 CA237624 NCI NIH HHS

• CTNNB1
• Hepatocarcinoma
• Mutation
• Next-generation sequencing
• Review
• TERT
• TP53

• Carcinoma, Hepatocellular/pathology
• High-Throughput Nucleotide Sequencing
• Humans
• Liver Neoplasms/pathology
• Mutation

• TERT
• TERT promoter C228T
• TERT promoter C250T
• cancer
• digital PCR
• gastrointestinal
• hepatobiliary
• telomerase

• HepG2 cell line
• hepatoblastoma
• hepatocellular carcinoma
• hepatocytes
• mutations

• HepG2 cell line
• hepatoblastoma
• hepatocellular carcinoma
• hepatocytes
• mutations

• HepG2 cell line
• hepatoblastoma
• hepatocellular carcinoma
• hepatocytes
• mutations

• Biomedical Research
• Hep G2 Cells
• Hepatocytes
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Metabolome
• Proteins/genetics
• Proteins/metabolism

• 20-14-00328 Russian Science Foundation

Liver cancer is one of the deadliest human cancers. Two of the most common molecular aberrations in liver cancer are: (1) activating mutations in the gene encoding β-catenin (CTNNB1); and (2) promoter mutations in telomerase reverse transcriptase (TERT). Here, we review recent findings regarding the interplay between TERT and β-catenin in order to better understand their role in liver cancer.

Hepatocellular carcinoma (HCC) is one of the deadliest human cancers. Activating mutations in the telomerase reverse transcriptase (TERT) promoter (TERTp) and CTNNB1 gene encoding β-catenin are widespread in HCC (~50% and ~30%, respectively). TERTp mutations are predicted to increase TERT transcription and telomerase activity. This review focuses on exploring the role of TERT and β-catenin in HCC and the current findings regarding their interplay. TERT can have contradictory effects on tumorigenesis via both its canonical and non-canonical functions. As a critical regulator of proliferation and differentiation in progenitor and stem cells, activated β-catenin drives HCC; however, inhibiting endogenous β-catenin can also have pro-tumor effects. Clinical studies revealed a significant concordance between TERTp and CTNNB1 mutations in HCC. In stem cells, TERT acts as a co-factor in β-catenin transcriptional complexes driving the expression of WNT/β-catenin target genes, and β-catenin can bind to the TERTp to drive its transcription. A few studies have examined potential interactions between TERT and β-catenin in HCC in vivo, and their results suggest that the coexpression of these two genes promotes hepatocarcinogenesis. Further studies are required with vertebrate models to better understand how TERT and β-catenin influence hepatocarcinogenesis.

• TERT
• TERT promoter
• hepatocellular carcinoma
• β-catenin

• R01 CA222570 NCI NIH HHS
• R01CA222570 NCI NIH HHS
• DRR-61-20 Damon Runyon Cancer Research Foundation

There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN).

We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated.

In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAF_mean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAF_mean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed.

Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.

The online version contains supplementary material available at 10.1186/s13046-021-02016-3.

• Circulating tumor DNA
• Hepatocellular carcinoma
• Lenvatinib

Cutaneous basal cell carcinoma (cBCC) is an economic burden to health services, due to its great morbidity and increasing incidence in old people. Infiltrative cBCCs and cBCCs with micronodular pattern are considered as more aggressive. The role of p53 expression and TERTp mutation on cBCC behavior remains to be clarified. We aimed to assess TERTp mutations and p53 expression in relation to the cBCC histological subtype in a cohort of patients referred to an ENT Department of a tertiary Hospital of Northern Portugal. We performed a retrospective clinicopathological and histological review of the head and neck cBCCs followed-up at the otorhinolaryngology department of Trás-os-Montes e Alto Douro hospital (January 2007–June 2018). We assessed TERTp mutations in 142 cBCCs and p53 protein expression, through immunohistochemistry, in 157 cBCCs. We detected TERTp mutations in 43.7% of cBCCs and p53 overexpression in 60.5% of cBCCs. We spotted association of p53 overexpression and TERTp mutation with necrosis. In the infitrative-growth pattern cBCCs, there was no significant association with the clinical and histological features evaluated, except for necrosis. In the indolent-growth cBCCs, we identified a significant association of TERTp mutation status with female sex, necrosis, multiple cBCCs, and p53 positive expression. Our results suggest that TERTp mutation may be useful to identify more aggressive features in the indolent-growth pattern cBCCs (nodular and superficial subtypes). Further studies with larger cohorts are warranted to clarify the relevance of TERTp mutation in cBCCs.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second leading cause of cancer-related deaths worldwide. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) are the major extrinsic risk factors of HCC development. Genetic background is pivotal in HCC pathogenesis, and both germline mutations and single nucleotide polymorphism (SNP) are intrinsic risk factors of HCC. These HCC risk factors predispose to hepatic injury and subsequent activation of fibrogenesis that progresses into cirrhosis and HCC. Probiotic bacteria can mitigate HCC risk by modulating host gut microbiota (GM) to promote growth of beneficial microbes and inhibit HCC-associated dysbiosis, thus preventing pathogen-associated molecular patterns (PAMPs)-mediated hepatic inflammation. Probiotics have antiviral activities against HBV and HCV infections, ameliorate obesity and risk of NAFLD/NASH, and their antioxidant, anti-proliferative, anti-angiogenic, and anti-metastatic effects can prevent the HCC pathogenesis. Probiotics also upregulate the expression of tumor suppressor genes and downregulate oncogene expression. Moreover, metabolites generated by probiotics through degradation of dietary phytochemicals may mitigate the risk of HCC development. These multiple anticancer mechanisms illustrate the potential of probiotics as an adjuvant strategy for HCC risk management and treatment.

• carcinogenesis
• liver cancer
• microbiome
• post-biotics
• probiotic bacteria

Hepatitis B virus (HBV) infection is a major global health problem causing acute and chronic liver disease that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) is essential for viral replication and the establishment of a persistent infection. Integrated HBV DNA represents another stable form of viral DNA regularly observed in the livers of infected patients. HBV DNA integration into the host genome occurs early after HBV infection. It is a common occurrence during the HBV life cycle, and it has been detected in all the phases of chronic infection. HBV DNA integration has long been considered to be the main contributor to liver tumorigenesis. The recent development of highly sensitive detection methods and research models has led to the clarification of some molecular and pathogenic aspects of HBV integration. Though HBV integration does not lead to replication-competent transcripts, it can act as a stable source of viral RNA and proteins, which may contribute in determining HBV-specific T-cell exhaustion and favoring virus persistence. The relationship between HBV DNA integration and the immune response in the liver microenvironment might be closely related to the development and progression of HBV-related diseases. While many new antiviral agents aimed at cccDNA elimination or silencing have been developed, integrated HBV DNA remains a difficult therapeutic challenge.

• HBV DNA integration
• HBsAg
• HBx
• chronic hepatitis B
• double-stranded DNA breaks
• hepatitis B virus infection
• oxidative stress

Hepatocellular carcinoma (HCC) is a malignant tumor without effective therapeutic drugs for most patients in advanced stages. Scutellariae Radix (SR) is a well-known anti-inflammatory and anticarcinogenic herbal medicine. However, the mechanism of SR against HCC remains to be clarified. In the present study, network pharmacology was utilized to characterize the mechanism of SR on HCC. The active components of SR and their targets were collected from the traditional Chinese medicine systems pharmacology database and the traditional Chinese medicine integrated database. HCC-related targets were acquired from the liver cancer databases OncoDB.HCC and Liverome. The gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway were analyzed using the Database for Annotation, Visualization, and Integrated Discovery. Component-component target and protein-protein interaction networks were set up. A total of 143 components of SR were identified, and 37 of them were considered as candidate active components. Fifty targets corresponding to 29 components of SR were mapped with targets of HCC. Functional enrichment analysis indicated that SR exerted an antihepatocarcinoma effect by regulating pathways in cancer, hepatitis B, viral carcinogenesis, and PI3K-Akt signaling. The holistic approach of network pharmacology can provide novel insights into the mechanistic study and therapeutic drug development of SR for HCC treatment.

• HSP
• Heat Shock Protein
• RNF128/GRAIL
• UPS
• Ubiquitin Proteasome System
• p53

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/genetics
• Gastrointestinal Neoplasms/pathology
• Humans
• Molecular Chaperones/antagonists & inhibitors
• Molecular Chaperones/metabolism
• Molecular Targeted Therapy/methods
• Mutation
• Protein Stability/drug effects
• Proteolysis/drug effects
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Ubiquitin-Protein Ligases/antagonists & inhibitors
• Ubiquitin-Protein Ligases/metabolism

• P30 CA046592 NCI NIH HHS
• R01 CA215596 NCI NIH HHS
• U54 CA163059 NCI NIH HHS

Molecular mechanisms underlying Hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) pathogenesis are still unclear. Therefore, we analyzed the levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and other oxidative lesions at codon 176 of the p53 gene, as well as the generation of 3-(2-deoxy-β-d-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M₁dG), in a cohort of HCV-related HCC patients from Italy. Detection of 8-oxodG and 5-hydroxycytosine (5-OHC) was performed by ligation mediated-polymerase chain reaction assay, whereas the levels of M₁dG were measured by chromatography and mass-spectrometry. Results indicated a significant 130% excess of 8-oxodG at –TGC– position of p53 codon 176 in HCV-HCC cases as compared to controls, after correction for age and gender, whereas a not significant increment of 5-OHC at –TGC– position was found. Then, regression models showed an 87% significant excess of M₁dG in HCV-HCC cases relative to controls. Our study provides evidence that increased adduct binding does not occur randomly on the sequence of the p53 gene but at specific sequence context in HCV-HCC patients. By-products of lipid peroxidation could also yield a role in HCV-HCC development. Results emphasize the importance of active oxygen species in inducing nucleotide lesions at a p53 mutational hotspot in HCV-HCC patients living in geographical areas without dietary exposure to aflatoxin B₁.

• 8-oxodG
• HCC
• HCV
• M1dG
• p53

• TERT promoter mutation
• hepatocellular carcinoma
• intrahepatic cholangiocarcinoma
• liver cancer
• telomerase
• telomere shortening

• GRK2254/C3 - HEIST Deutsche Forschungsgemeinschaft
• GU 569/6-1 Deutsche Forschungsgemeinschaft