• Genetics
• apoptosis
• hepatocellular carcinoma.
• liver cancer
• polymorphism
• proliferation

• Humans
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Polymorphism, Genetic
• Genetic Predisposition to Disease

• RNA sequencing
• TERT promoter C228T and C250T mutations
• differential gene expression analysis
• pan-cancer investigation
• pathway activation profiling
• reverse transcriptase

• Russian Science Foundation
• Ministry of Science and Higher Education of the Russian Federation

• Humans
• Carcinoma, Hepatocellular/secondary
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/secondary
• Liver Neoplasms/pathology
• Neoplasms, Unknown Primary/pathology
• Shoulder

• Atypical hepatocellular neoplasm
• Dysplastic nodule
• Hepatocellular adenoma

• Humans
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/etiology
• Liver Neoplasms/diagnosis
• Liver Neoplasms/etiology
• Liver Cirrhosis/etiology
• Liver Cirrhosis/pathology
• Precancerous Conditions/pathology

• Circulating tumour cell
• HCC biomarkers
• cell signaling pathways
• immunotherapy
• multi-omics technology

• Humans
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/therapy
• Molecular Targeted Therapy
• Mutation/genetics

• biomarkers
• diagnostic imaging
• hepatocellular carcinoma
• pathology
• precancerous conditions

• cstc2018jcyjAX0181 Basic Research and Frontier Exploration Project of Chongqing Science and Technology Com-mission

• Cellular reprogramming
• Cholangiocarcinoma
• Epigenetics
• Hepatocellular carcinoma
• Liver progenitor cell
• Transdifferentiation

• Humans
• Cell Plasticity
• DNA Methylation
• Cell Proliferation
• Liver/metabolism
• Liver Neoplasms/genetics

• P30 DK120531 NIDDK NIH HHS
• R01 CA258449 NCI NIH HHS

• TERT promoter mutations
• circRNA
• hepatocellular carcinoma
• lncRNA
• microRNA

• National Natural Science Foundation of China
• Nature Science Foundation of Shandong Province
• Province of China and the Cheeloo Youth Program of Shandong University to Xiaolu Zhang, the Fundamental Research Funds of Shandong University to Jingya Yu

• ICI
• TERT
• Telomerase
• carcinogenesis
• genitourinary
• glioma
• immunotherapy
• urothelial carcinoma

Molecular biomarkers play a marginal role in clinical practice for hepatocellular carcinoma (HCC) diagnosis, surveillance and treatment monitoring. Radiological biomarker: alpha-fetoprotein is still a lone protagonist in this field. The potential role of molecular biomarkers in the assessment of prognosis and treatment results could reduce the health costs faced by standard radiology. The majority of efforts are oriented towards early HCC detection, but the field faces an important challenge to find adequate biomarkers for advanced HCC management.

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the fourth cause of tumor-related death. Imaging biomarkers are based on computed tomography, magnetic resonance, and contrast-enhanced ultrasound, and are widely applied in HCC diagnosis and treatment monitoring. Unfortunately, in the field of molecular biomarkers, alpha-fetoprotein (AFP) is still the only recognized tool for HCC surveillance in both diagnostic and follow-up purposes. Other molecular biomarkers have little roles in clinical practice regarding HCC, mainly for the detection of early-stage HCC, monitoring the response to treatments and analyzing tumor prognosis. In the last decades no important improvements have been achieved in this field and imaging biomarkers maintain the primacy in HCC diagnosis and follow-up. Despite the still inconsistent role of molecular biomarkers in surveillance and early HCC detection, they could play an outstanding role in prognosis estimation and treatment monitoring with a potential reduction in health costs faced by standard radiology. An important challenge resides in identifying sufficiently sensitive and specific biomarkers for advanced HCC for prognostic evaluation and detection of tumor progression, overcoming imaging biomarker sensitivity. The aim of this review is to analyze the current molecular and imaging biomarkers in advanced HCC.

Hepatocellular carcinoma (HCC) represents the primary carcinoma of the liver and the fourth leading cause of cancer-related deaths. The World Health Organization estimates an increase in cases in the coming years. The risk factors of HCC are multiple, and the incidence in different countries is closely related to the different risk factors to which the population is exposed. The molecular mechanisms that drive HCC tumorigenesis are extremely complex, but understanding this multistep process is essential for the identification of diagnostic, prognostic, and therapeutic markers. The development of multigenic next-generation sequencing panels through the parallel analysis of multiple markers can provide a landscape of the genomic status of the tumor. Considering the literature and our preliminary data based on 36 HCCs, the most frequently altered genes in HCCs are TERT, CTNNB1, and TP53. Over the years, many groups have attempted to classify HCCs on a molecular basis, but a univocal classification has never been achieved. Nevertheless, statistically significant correlations have been found in HCCs between the molecular signature and morphologic features, and this leads us to think that it would be desirable to integrate the approach between anatomic pathology and molecular laboratories.

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

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

The management of chronic liver diseases (CLDs) remains a challenge, and identifying effective treatments is a major unmet medical need. In the current review we focus on the pituitary tumor transforming gene (PTTG1)/delta like non-canonical notch ligand 1 (DLK1) axis as a potential therapeutic target to attenuate the progression of these pathological conditions. PTTG1 is a proto-oncogene involved in proliferation and metabolism. PTTG1 expression has been related to inflammation, angiogenesis, and fibrogenesis in cancer and experimental fibrosis. On the other hand, DLK1 has been identified as one of the most abundantly expressed PTTG1 targets in adipose tissue and has shown to contribute to hepatic fibrosis by promoting the activation of hepatic stellate cells. Here, we extensively analyze the increasing amount of information pointing to the PTTG1/DLK1 signaling pathway as an important player in the regulation of these disturbances. These data prompted us to hypothesize that activation of the PTTG1/DLK1 axis is a key factor upregulating the tissue remodeling mechanisms characteristic of CLDs. Therefore, disruption of this signaling pathway could be useful in the therapeutic management of CLDs.

• Differential diagnosis
• Hepatoblastoma
• Hepatocellular carcinoma
• Molecular pathology
• Rhabdoid tumor

• Carcinoma, Hepatocellular/pathology
• Child
• Gastrointestinal Neoplasms
• Hepatoblastoma/pathology
• Humans
• Liver Neoplasms/pathology
• World Health Organization

With a growing amount of (multi-)omics data being available, the extraction of knowledge from these datasets is still a difficult problem. Classical enrichment-style analyses require predefined pathways or gene sets that are tested for significant deregulation to assess whether the pathway is functionally involved in the biological process under study. De novo identification of these pathways can reduce the bias inherent in predefined pathways or gene sets. At the same time, the definition and efficient identification of these pathways de novo from large biological networks is a challenging problem.

We present a novel algorithm, DeRegNet, for the identification of maximally deregulated subnetworks on directed graphs based on deregulation scores derived from (multi-)omics data. DeRegNet can be interpreted as maximum likelihood estimation given a certain probabilistic model for de-novo subgraph identification. We use fractional integer programming to solve the resulting combinatorial optimization problem. We can show that the approach outperforms related algorithms on simulated data with known ground truths. On a publicly available liver cancer dataset we can show that DeRegNet can identify biologically meaningful subgraphs suitable for patient stratification. DeRegNet can also be used to find explicitly multi-omics subgraphs which we demonstrate by presenting subgraphs with consistent methylation-transcription patterns. DeRegNet is freely available as open-source software.

The proposed algorithmic framework and its available implementation can serve as a valuable heuristic hypothesis generation tool contextualizing omics data within biomolecular networks.

• Biomolecular networks
• De-novo subnetwork enrichment
• Fractional integer programming
• Functional enrichment
• Omics data

• high-throughput nucleotide sequencing
• immunohistochemistry
• liver cell adenoma
• male

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/virology
• Computational Biology/methods
• Hepatitis B/genetics
• Hepatitis B virus/physiology
• High-Throughput Nucleotide Sequencing
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/virology
• Sequence Analysis, DNA
• Sequence Analysis, RNA
• Software
• Virus Integration
• Exome Sequencing
• Workflow

• Mayo Clinic Center for Individualized Medicine

• cell-free DNA
• copy number
• early cancer
• hepatocellular carcinoma
• premalignant lesions
• tumour pathology

• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/diagnosis
• Cell-Free Nucleic Acids
• Circulating Tumor DNA/blood
• DNA Copy Number Variations
• Humans
• Liver Diseases/blood
• Liver Diseases/diagnosis
• Liver Neoplasms/blood
• Liver Neoplasms/diagnosis
• Precancerous Conditions/blood
• Precancerous Conditions/diagnosis

• MR/N005953/1 Medical Research Council

• H-HCA, HNF1α-mutated HCAs
• HCA, hepatocellular adenoma
• HCC, hepatocellular carcinoma
• Hepatocellular adenoma
• IHCA, inflammatory HCA
• LFABP, liver fatty acid binding protein
• LR, liver resection
• MT-HCA, malignant transformation HCA
• NP-HCC, HCC occurring on normal parenchyma
• RFS, recurrence-free survival
• SF-HCA, small foci of malignant transformation HCA
• U-HCA, unclassified HCA
• liver resection
• malignant transformation
• recurrence
• β-HCA, β-catenin-mutated HCA
• β-IHCA, β-catenin-mutated inflammatory HCA

Activating mutations in the promoter region of TERT (TERTp) gene are frequently observed in low- and high-grade dysplastic nodules and defined as early events in hepatocellular carcinoma development. This study shows that the nucleotide change G>A at position −124 in the TERTp region is very common in hepatocellular carcinoma. The concordance rate between droplet digital PCR (ddPCR) (63.6%) and Sanger sequencing (52.1%) detection methods is good (83.5%). HCC patients carrying the TERTp mutation had lower levels of the tumour biomarker Ca19-9 but showed reduced survival. The presence of TERTp mutations may represent a prognostic signature in liver cancer.

Telomerase reactivation during hepatocarcinogenesis is recurrently caused by two point mutations occurring most frequently at the nucleotide −124 (95%) and occasionally at the nucleotide −146 (<5%) upstream of the TERT translational start site in hepatocellular carcinoma (HCC). In this study, we designed a droplet digital PCR (ddPCR) assay to detect TERT promoter (TERTp) nucleotide change G>A at position −124 and to quantify the mutant allele frequency (MAF) in 121 primary liver cancers, including 114 HCC along with 23 autologous cirrhotic tissues, five cholangiocarcinoma (CC), and two hepato-cholangiocarcinoma (HCC-CC). All cases were evaluated for tumour markers such as α-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA). We compared the sensitivity of ddPCR and Sanger sequencing and investigated the prognostic relevance of TERTp mutations. The TERTp G>A transition was identified in 63.6% and 52.1% of HCC samples by ddPCR and Sanger sequencing, respectively. One out of 23 (4.3%) peri-tumour tissues tested positive only by ddPCR. One out of five CC (20%) and none of the HCC-CC were found concordantly mutated by the two methods. The TERTp MAF ranged from 2% to 66%, and the large majority (85.5%) of mutated samples showed a value above 20%. A statistically significant correlation was found between TERTp mutation and tumour size (p = 0.048), while an inverse correlation was observed with CA19-9 levels (p = 0.0105). Moreover, HCC patients with TERTp −124A had reduced survival. In conclusion, the single nucleotide variation G>A at position −124 in TERTp, detected either by ddPCR or by Sanger sequencing, showed a remarkable high frequency in HCC. Such mutation is associated with lower levels of CA19-9 and reduced survival in HCC patients suggesting that the TERTp status may represent a distinct signature of liver cancer subgroups.

• HBV
• HCC
• HCV
• TERT promoter
• TERTp
• cirrhosis
• ddPCR
• droplet digital PCR
• hepatitis B virus
• hepatitis C virus
• hepatocellular carcinoma
• mutation

• 2D cell lines
• 3D tumor spheroids
• artificial intelligence algorithms
• hepatocellular carcinoma
• in silico
• machine learning
• mouse models
• organ-on-a-chip
• organoids

• disease prevention
• health disparities
• hepatobiliary diseases
• precision medicine

• Aged
• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/ethnology
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell-Free Nucleic Acids/blood
• Cell-Free Nucleic Acids/genetics
• Female
• High-Throughput Nucleotide Sequencing
• Hispanic or Latino/genetics
• Humans
• Liver Cirrhosis/blood
• Liver Cirrhosis/ethnology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Liver Neoplasms/blood
• Liver Neoplasms/ethnology
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Male
• Mutation

• R01 CA204665 NCI NIH HHS
• UL1 TR003167 NCATS NIH HHS
• CA016672 NCI NIH HHS
• R01CA204665 NCI NIH HHS

• Telomerase
• hepatocellular carcinoma
• lipid metabolism
• liver fibrosis
• metabolic disorders
• nonalcoholic fatty liver disease
• therapeutic targets

• Hepatocellular carcinoma
• Methylation
• Mutation
• ctDNA

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Circulating Tumor DNA/genetics
• Humans
• Liquid Biopsy/methods
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Medical Oncology
• Precision Medicine

• 82002539 the National Natural Science Foundation of China
• 19ZR1447700 Natural Science Foundation of Shanghai
• PTKWWS201801, PTKWWS201903 Health System Innovation Project of Shanghai Putuo Science and Technology Commission
• CFHPC2019031 WBN Hepatology Research Fund of China Hepatitis Prevention and Treatment Foundation
• 20YF1443300 Yangfan plan of Shanghai science and technology commission
• Natural Science Foundation of Shanghai

Hepatocellular carcinoma (HCC) recurrence is the major obstacle concerning patients’ survival. Tertiary prevention by antiviral therapies could reduce HCC recurrence rate in both chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infected patients. In chronic hepatitis B (CHB) patients, nucleos(t)ide analogues (Nuc) provide a more effective HCC tertiary prevention effect than an interferon (IFN)-based regimen. In chronic hepatitis C (CHC) patients, the tertiary prevention effect by direct acting antiviral agents (DAAs) was reported non-inferior to that by IFN-based therapy. Chronic hepatitis C patients left untreated had the worst survival benefit as well as shorted recurrence-free interval than those treated by either type of antiviral regimen. Although the risk of HCC recurrence could only be decreased but not diminished by antiviral therapies due to host and microenvironmental factors beyond virus infection, antiviral therapy helps to preserve and improve liver function which makes multi-modality anticancer treatment feasible to improve survival.

Hepatocellular carcinoma (HCC) ranks as a leading cause of common cancer and cancer-related death. The major etiology of HCC is due to chronic hepatitis virus including HBV and HCV infections. Scheduled HCC surveillance in high risk populations improves the early detection rate and the feasibility of curative treatment. However, high HCC recurrence rate still accounts for the poor prognosis of HCC patients. In this article, we critically review the pathogenesis of viral hepatitis-related hepatocellular carcinoma and the evidence of tertiary prevention efficacy by current available antiviral treatment, and discuss the knowledge gap in viral hepatitis-related HCC tertiary prevention.

• carcinogenesis
• cirrhosis
• direct acting antiviral agents
• interferon
• nucleos(t)ide analogues
• sustained virologic response

• Hepatobiliary-clinical
• cancer genomics
• circulating tumor DNA
• droplet digital PCR
• hepatocellular carcinoma
• oncology-clinical

• HCC
• carcinogenesis
• genomics
• liver cancer
• mutation
• therapeutics

• K08 CA222676 NCI NIH HHS

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.

• Chronic viral infection
• Hallmarks of cancer
• Hepatocellular carcinoma
• Hepatitis B virus
• Hepatitis C virus
• Hepatitis delta virus co-infection
• Molecular mechanisms
• Viral hepatitis

• Carcinoma, Hepatocellular
• Hepatitis B/complications
• Hepatitis B virus/genetics
• Hepatitis, Viral, Human
• Humans
• Liver Neoplasms

• Cre recombinase
• Lgr5
• clonality
• field cancerization
• metaplasia
• stem cells

• Animals
• Basic Helix-Loop-Helix Transcription Factors/genetics
• Bile Duct Neoplasms/pathology
• Carcinogenesis/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Pancreatic Ductal/pathology
• Cholangiocarcinoma/pathology
• Disease Models, Animal
• Gastrointestinal Tract/pathology
• Humans
• Liver Neoplasms/pathology
• Metaplasia/pathology
• Mice
• Mutation
• Neoplastic Stem Cells/pathology
• Pancreas/pathology
• Pancreatic Neoplasms/pathology
• Precancerous Conditions
• Proto-Oncogene Proteins p21(ras)/genetics
• Receptors, G-Protein-Coupled/genetics
• Tumor Suppressor Protein p53/genetics

• HCC
• cancer-related genetic change
• histopathology
• imaging findings
• multistep carcinogenesis

Wnt/β-catenin-mediated signaling is a key pathway regulating tissue growth and development, and tumorigenesis, and has received increasing attention in recent years. In addition to participating in healthy tissue and organ development, ectopic activation of the pathway can cause a variety of tumors and other pathologies. The pathway plays a critical role in many processes such as proliferation, differentiation, apoptosis, migration, invasion, epithelial–mesenchymal transition and cancer cell stemness. The importance of the Wnt signal is self-evident. This review describes the underlying mechanism of Wnt signaling pathway and highlights the latest findings on the relationship between Wnt signaling pathway and tumorigenesis. In addition, the potential relationship between miRNAs and Wnt signaling is presented. Furthermore, we discuss the intrinsic link between Wnt signaling and cancer cell stemness, which shed light on the malignant progression of tumor cells. Finally, cancer treatment strategies based on the canonical Wnt signaling pathway are summarized, hoping to help clinical development.

• Wnt/β-catenin
• cancer stem cell
• miRNAs
• target
• therapeutic strategy
• tumor

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

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

Hepatocellular carcinoma is a malignant disease with improved hepatic regeneration and survival, and is activated by human telomere transferase (hTERT). hTERT is expressed during early fetal development and switched off in most adult tissues, but it becomes reactivated in HCC. The exact mechanism regulating these expression changes remains unknown during HCC progress. We evaluated the relationship between hTERT expression and human kruppel-related 3 (HKR3) and cell cycle-related factors in HCC cell lines. Following transfection for hTERT knockdown and HKR3 overexpression, proteomic and transcriptomic analyses related to hTERT were performed using liquid chromatography/mass spectrometry (LC/MS) and RNA sequencing (RNAseq) in HCC cell lines. The expression levels of hTERT, HKR3, and cell cycle-related factors were measured using western blotting, and tumor growth were evaluated via cell proliferation and cell cycle assays. Transcriptomic and proteomic analyses showed that HKR3, hTERT and cyclin-dependent kinase inhibitor 2A (CDKN2A) were correlated. Up-regulation of HKR3 expression decreased hTERT and cyclin activation and suppressed the G1/S phase of the cell cycle through CDKN2A activation. Our results suggest that HKR3 induced regulation of cell cycle through hTERT inhibition and CDKN2A activation. Our results will facilitate further exploration of the pathways regulating human telomerase activity in HCC cell lines.

• CDKN2A
• Cell cycle
• HKR3
• Hepatocellular carcinoma
• hTERT

• CTNNB1 gene
• TERT promoter
• TP53 gene
• activating protein 2 transcription factor
• hepatocellular carcinoma
• somatic mutations

• Autophagy
• Cirrhosis
• Drug-Induced Liver Injury
• Inflammation
• Model Organisms
• Tumor Microenvironment

• Animals
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Disease Models, Animal
• Gene Regulatory Networks
• Genetic Predisposition to Disease
• Hormones/metabolism
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Mutation
• Tumor Microenvironment
• Zebrafish

• R03 DK085445 NIDDK NIH HHS
• R24 OD017870 NIH HHS
• F32 AA025271 NIAAA NIH HHS
• F32 AA027135 NIAAA NIH HHS
• R01 DK105198 NIDDK NIH HHS
• R01 DK090311 NIDDK NIH HHS

• FGF19
• Fluorescence in situ hybridization
• Hepatocellular carcinoma
• High copy number amplification
• Prognosis

Telomerase reverse transcriptase (TERT) promotes immortalization by protecting telomeres in cancer cells. Mutation of the TERT promoter is one of the most common genetic alterations in hepatocellular carcinoma (HCC), indicating that TERT upregulation is a critical event in hepatocarcinogenesis. Regulators of TERT transcription are, therefore, predicted to be plausible targets for HCC treatment. We undertook a genome‐wide shRNA library screen and identified C15orf55 and C7orf43 as regulators of TERT expression in HepG2 cells. Promoter assays showed that C15orf55‐ and C7orf43‐responsive sites exist between base pairs −58 and +36 and −169 and −59 in the TERT promoter, respectively. C15orf55 upregulates TERT expression by binding to two GC motifs in the SP1 binding site of the TERT promoter. C7orf43 upregulates TERT expression through Yes‐associated protein 1. The expression levels of C15orf55 and C7orf43 also correlated with that of TERT, and were significantly increased in both HCC tissues and their adjacent non‐tumor tissues, compared to normal liver tissues from non‐HCC patients. Analysis of 377 HCC patients in The Cancer Genome Atlas dataset showed that overall survival of patients with low levels of C15orf55 and C7orf43 expression in tumor tissues was better compared with patients with high levels of C15orf55 and/or high C7orf43 expression. These results indicate that C15orf55 and C7orf43 are involved in the incidence and progression of HCC by upregulating TERT. In conclusion, we identified C15orf55 and C7orf43 as positive regulators of TERT expression in HCC tissues. These genes are promising targets for HCC treatment.

• C15orf55
• C7orf43
• hepatocellular carcinoma
• telomerase reverse transcriptase
• transcription

Signaling of the receptor tyrosine kinase Axl and its ligand Gas6 is crucially involved in the development of liver fibrosis and hepatocellular carcinoma (HCC) by activation of hepatic stellate cells and modulation of hepatocyte differentiation. Shedding of Axl’s ectodomain leads to the release of soluble Axl (sAxl), which is increased in advanced fibrosis and in early-to-late stage HCC in the presence and absence of cirrhosis. Here, we focus on the dynamics of Axl receptor shedding and delineate possible scenarios how Axl signaling might act as driver of fibrosis progression and HCC development. Based on experimental and clinical data, we discuss the consequences of modifying Axl signaling by sAxl cleavage, as well as cellular strategies to escape from antagonizing effects of Axl shedding by the involvement of the hepatic microenvironment. We emphasize a correlation between free Gas6 and free sAxl levels favoring abundant Gas6/Axl signaling in advanced fibrosis and HCC. The raised scenario provides a solid basis for theranostics allowing the use of sAxl as an accurate diagnostic biomarker of liver cirrhosis and HCC, as well as Axl receptor signaling for therapeutic intervention in stratified HCC patients.

• Axl
• Gas6
• hepatocellular carcinoma
• shedding
• soluble Axl
• theranostics

• Hepatocellular carcinoma
• cancer metabolism
• drug resistance
• positron emission tomography/computed tomography (PET/CT)

• Acetates
• Adult
• Aged
• Biomarkers, Tumor/metabolism
• Carbon
• Carcinoma, Hepatocellular/diagnostic imaging
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Female
• Fluorodeoxyglucose F18/metabolism
• Humans
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Positron Emission Tomography Computed Tomography/methods
• Positron-Emission Tomography
• Radiopharmaceuticals/metabolism

• National Research Foundation of Korea
• Incheon National University

Transfer of genetic material from microbes or viruses into the host genome is known as horizontal gene transfer (HGT). The integration of viruses into the human genome is associated with multiple cancers, and these can now be detected using next-generation sequencing methods such as whole genome sequencing and RNA-sequencing.

We designed a novel computational workflow, HGT-ID, to identify the integration of viruses into the human genome using the sequencing data. The HGT-ID workflow primarily follows a four-step procedure: i) pre-processing of unaligned reads, ii) virus detection using subtraction approach, iii) identification of virus integration site using discordant and soft-clipped reads and iv) HGT candidates prioritization through a scoring function. Annotation and visualization of the events, as well as primer design for experimental validation, are also provided in the final report. We evaluated the tool performance with the well-understood cervical cancer samples. The HGT-ID workflow accurately detected known human papillomavirus (HPV) integration sites with high sensitivity and specificity compared to previous HGT methods. We applied HGT-ID to The Cancer Genome Atlas (TCGA) whole-genome sequencing data (WGS) from liver tumor-normal pairs. Multiple hepatitis B virus (HBV) integration sites were identified in TCGA liver samples and confirmed by HGT-ID using the RNA-Seq data from the matched liver pairs. This shows the applicability of the method in both the data types and cross-validation of the HGT events in liver samples. We also processed 220 breast tumor WGS data through the workflow; however, there were no HGT events detected in those samples.

HGT-ID is a novel computational workflow to detect the integration of viruses in the human genome using the sequencing data. It is fast and accurate with functions such as prioritization, annotation, visualization and primer design for future validation of HGTs. The HGT-ID workflow is released under the MIT License and available at http://kalarikrlab.org/Software/HGT-ID.html.

• Horizontal gene transfer
• Next-generation sequencing
• RNA-Seq – Cancer
• Viral integration
• Whole-genome sequencing