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Bourganou MV, Chondrogianni ME, Kyrou I, Flessa CM, Chatzigeorgiou A, Oikonomou E, Lambadiari V, Randeva HS, Kassi E. Unraveling Metabolic Dysfunction-Associated Steatotic Liver Disease Through the Use of Omics Technologies. Int J Mol Sci 2025; 26:1589. [PMID: 40004054 PMCID: PMC11855544 DOI: 10.3390/ijms26041589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is the most prevalent liver disorder globally, linked to obesity, type 2 diabetes, and cardiovascular risk. Understanding its potential progression from simple steatosis to cirrhosis and hepatocellular carcinoma (HCC) is crucial for patient management and treatment strategies. The disease's complexity requires innovative approaches for early detection and personalized care. Omics technologies-such as genomics, transcriptomics, proteomics, metabolomics, and exposomics-are revolutionizing the study of MASLD. These high-throughput techniques allow for a deeper exploration of the molecular mechanisms driving disease progression. Genomics can identify genetic predispositions, whilst transcriptomics and proteomics reveal changes in gene expression and protein profiles during disease evolution. Metabolomics offers insights into the metabolic alterations associated with MASLD, while exposomics links environmental exposures to MASLD progression and pathology. By integrating data from various omics platforms, researchers can map out the intricate biochemical pathways involved in liver disease progression. This review discusses the roles of omics technologies in enhancing the understanding of disease progression and highlights potential diagnostic and therapeutic targets within the MASLD spectrum, emphasizing the need for non-invasive tools in disease staging and treatment development.
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Affiliation(s)
- Maria V. Bourganou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.V.B.); (M.E.C.); (C.-M.F.)
| | - Maria Eleni Chondrogianni
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.V.B.); (M.E.C.); (C.-M.F.)
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Ioannis Kyrou
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Centre for Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
- College of Health, Psychology and Social Care, University of Derby, Derby DE22 IGB, UK
| | - Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.V.B.); (M.E.C.); (C.-M.F.)
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece;
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, “Sotiria” Thoracic Diseases Hospital of Athens, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Vaia Lambadiari
- 2nd Department of Internal-Medicine, Diabetes Centre, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Centre for Health & Life Sciences, Coventry University, Coventry CV1 5FB, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.V.B.); (M.E.C.); (C.-M.F.)
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Murugan AK, Kannan S, Alzahrani AS. TERT promoter mutations in gliomas: Molecular roles in tumorigenesis, metastasis, diagnosis, prognosis, therapeutic targeting, and drug resistance. Biochim Biophys Acta Rev Cancer 2025; 1880:189243. [PMID: 39674418 DOI: 10.1016/j.bbcan.2024.189243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 12/06/2024] [Accepted: 12/08/2024] [Indexed: 12/16/2024]
Abstract
Telomerase reverse transcriptase (TERT), a critical player in cellular immortalization, has emerged as a focal point of investigation due to its frequent promoter mutations in various human malignancies. TERT promoter mutations exhibit a significant role in tumorigenesis, fostering unbridled cellular proliferation and survival. This comprehensive review delves into the landscape of TERT promoter mutations and their profound implications in cancer, particularly within the context of gliomas. This article meticulously examines the intricate interplay between TERT promoter mutations and the metastatic cascade, shedding light on their capacity to orchestrate invasive behavior in gliomas. Moreover, this review describes the recent trends in therapeutic targeting of the TERT and dissects the evolving landscape of drug resistance associated with TERT mutations, providing insights into potential therapeutic challenges. In addition, the diagnostic and prognostic implications of TERT promoter mutations in gliomas are scrutinized, unraveling their potential as robust biomarkers. It also discusses the recent advancements in molecular diagnostics, illustrating the promise of TERT mutations as diagnostic tools and prognostic indicators. This review collectively aims to contribute to a deeper understanding of TERT promoter mutations in gliomas, offering a foundation for future research endeavors and paving the way for innovative strategies in glioma management.
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Affiliation(s)
- Avaniyapuram Kannan Murugan
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
| | - Siddarth Kannan
- School of Medicine, University of Central Lancashire, Preston PR1 2HE, UK
| | - Ali S Alzahrani
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
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Armandi A, Rosso C, Caviglia GP, Bugianesi E. An updated overview on hepatocellular carcinoma in patients with Metabolic dysfunction-Associated Steatotic Liver Disease: Trends, pathophysiology and risk-based surveillance. Metabolism 2025; 162:156080. [PMID: 39571891 DOI: 10.1016/j.metabol.2024.156080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 11/25/2024]
Abstract
Hepatocellular carcinoma (HCC) is a relevant complication occurring in individuals with advanced Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Recent epidemiological data suggest an alarming increase in the HCC burden worldwide, with a relevant proportion attributable to MASLD (up to 38 %), either in cirrhotic or non-cirrhotic livers. In view of the changing landscape of metabolic syndrome as "silent pandemic", this narrative review aims to provide an updated picture of the burden of HCC in individuals with MASLD. In the complex pathophysiological pathways linking insulin resistance to MASLD and cardiometabolic syndrome, metabolic inflammation appears a relevant driver of systemic as well as organ-specific complications. Novel insights from the field of immunology, gut-derived liver damage, and association with extra-hepatic cancers will be discussed. Finally, strategies for risk-based HCC surveillance (circulating biomarkers, prognostic models and polygenic risk scores) will be provided and the potential impact of novel drug targeting fibrosing Metabolic dysfunction-Associated Steatohepatitis (MASH) on incident HCC will be discussed.
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Affiliation(s)
- Angelo Armandi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Torino, Italy.
| | - Chiara Rosso
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Torino, Italy.
| | - Gian Paolo Caviglia
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Torino, Italy.
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Torino, Italy.
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Liu M, Wen Y. Point-of-care testing for early-stage liver cancer diagnosis and personalized medicine: Biomarkers, current technologies and perspectives. Heliyon 2024; 10:e38444. [PMID: 39397977 PMCID: PMC11470528 DOI: 10.1016/j.heliyon.2024.e38444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 09/21/2024] [Accepted: 09/24/2024] [Indexed: 10/15/2024] Open
Abstract
Liver cancer is a highly prevalent and lethal form of cancer worldwide. In the absence of early diagnosis, treatment options for this disease are severely restricted. Recent advancements in genomics and bioinformatics have facilitated the discovery of a multitude of novel biomarkers that accurately depict an individual's disease diagnosis, progression, and treatment response. Leveraging these breakthroughs, personalized medicine employs an individual's biomarker profile to enable early detection of liver cancer and inform decisions regarding treatment selection, dosage determination, and prognosis assessment. The current lack of readily applicable, timely, and economically viable tools for biomarker analysis has hindered the incorporation of personalized medicine into regular clinical procedures. Over the past decade, significant advancements have been achieved in the field of molecular point-of-care testing (POCT) and amplification techniques, leading to substantial improvements in the diagnosis of liver cancer and the implementation of precision medicine. Instrument-free PCR technology or plasma PCR technology can shorten the complex procedure of in vitro detection of nucleic acid-based biomarkers. Also, compared to traditional ELISA, various nanomaterials modified with monoclonal antibodies to target proteins for recognition, capture, and detection have improved the efficiency of protein-based biomarker detection. These advances have reduced the time and cost of clinical detection of early-stage hepatocellular carcinoma and improved the efficiency of timely diagnosis and survival of suspected patients while reducing unnecessary testing costs and procedures. This review aims to provide a comprehensive overview of the current and emerging biomarkers employed in the early detection of liver cancer, as well as the advancements in point-of-care molecular testing technology and platforms. The primary objective is to assess their potential in facilitating the implementation of personalized medicine. This review ultimately revealed that the diagnosis of early-stage hepatocellular carcinoma not only requires sensitive biomarkers, but its various modifications and changes during the progression of cirrhosis to early-stage hepatocellular carcinoma will be a greater focus of our attention in the future. The rapid development of POCT has facilitated the opportunity to readily detect liver cancer in the general population in the future, and the integration of multi-pathway multiplexing and intelligent algorithms has improved the sensitivity and accuracy of early liver cancer biomarker detection. It is expected that the integration of point-of-care technology will be instrumental in the widespread adoption of personalized medicine in the foreseeable future.
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Affiliation(s)
- Mengxiang Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Yanrong Wen
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China
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Abdelhameed F, Kite C, Lagojda L, Dallaway A, Chatha KK, Chaggar SS, Dalamaga M, Kassi E, Kyrou I, Randeva HS. Non-invasive Scores and Serum Biomarkers for Fatty Liver in the Era of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): A Comprehensive Review From NAFLD to MAFLD and MASLD. Curr Obes Rep 2024; 13:510-531. [PMID: 38809396 PMCID: PMC11306269 DOI: 10.1007/s13679-024-00574-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2024] [Indexed: 05/30/2024]
Abstract
PURPOSE OF REVIEW The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide, making it the leading cause of liver related morbidity and mortality. Currently, liver biopsy is the gold standard for assessing individuals with steatohepatitis and fibrosis. However, its invasiveness, sampling variability, and impracticality for large-scale screening has driven the search for non-invasive methods for early diagnosis and staging. In this review, we comprehensively summarise the evidence on the diagnostic performance and limitations of existing non-invasive serum biomarkers and scores in the diagnosis and evaluation of steatosis, steatohepatitis, and fibrosis. RECENT FINDINGS Several non-invasive serum biomarkers and scores have been developed over the last decade, although none has successfully been able to replace liver biopsy. The introduction of new NAFLD terminology, namely metabolic dysfunction-associated fatty liver disease (MAFLD) and more recently metabolic dysfunction-associated steatotic liver disease (MASLD), has initiated a debate on the interchangeability of these terminologies. Indeed, there is a need for more research on the variability of the performance of non-invasive serum biomarkers and scores across the diagnostic entities of NAFLD, MAFLD and MASLD. There remains a significant need for finding valid and reliable non-invasive methods for early diagnosis and assessment of steatohepatitis and fibrosis to facilitate prompt risk stratification and management to prevent disease progression and complications. Further exploration of the landscape of MASLD under the newly defined disease subtypes is warranted, with the need for more robust evidence to support the use of commonly used serum scores against the new MASLD criteria and validation of previously developed scores.
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Affiliation(s)
- Farah Abdelhameed
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | - Chris Kite
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- School of Health and Society, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, WV1 1LY, UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, CV1 5FB, UK
- Chester Medical School, University of Chester, Shrewsbury, SY3 8HQ, UK
| | - Lukasz Lagojda
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Clinical Evidence-Based Information Service (CEBIS), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | - Alexander Dallaway
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- School of Health and Society, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, WV1 1LY, UK
| | - Kamaljit Kaur Chatha
- Department of Biochemistry and Immunology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | | | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- First Department of Propaupedic and Internal Medicine, Endocrine Unit, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, CV1 5FB, UK.
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.
- College of Health, Psychology and Social Care, University of Derby, Derby, DE22 1GB, UK.
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855, Athens, Greece.
| | - Harpal S Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, CV1 5FB, UK.
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
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Tsuruoka M, Ninomiya M, Inoue J, Iwata T, Sano A, Sato K, Onuki M, Sawahashi S, Masamune A. Changes in Mutations of Cell-Free DNA and Liver Tumor Tissue in Patients with Advanced Hepatocellular Carcinoma before and after Introduction of Lenvatinib. Oncology 2024; 102:1072-1083. [PMID: 39047713 PMCID: PMC11614310 DOI: 10.1159/000540438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 07/07/2024] [Indexed: 07/27/2024]
Abstract
INTRODUCTION Cell-free DNA (cfDNA) is expected to contribute to the decision for treatment and prediction of effects with minimally invasion. We investigated the correlation between gene mutations before and after lenvatinib (LEN) treatment and its effectiveness, in order to find advanced hepatocellular carcinoma (HCC) patients who would benefit greatly from the therapy. METHODS We analyzed cfDNA before and 6-8 weeks after the start of treatment in 20 advanced HCC patients who started LEN. A next-generation sequencer was used for CTNNB1 and TP53. Concerning TERT promoter, -124C>T and -146C>T mutations are researched using digital PCR. In addition, we examined liver tumor biopsy tissues by the same method. Computerized tomography evaluation was performed at 6-8 weeks and 3-4 months to assess the efficacy. RESULTS Frequencies of TERT promoter, CTNNB1, and TP53 mutations in pretreatment cfDNA were 45%, 65%, and 65%, but 53%, 41%, and 47% in HCC tissues, respectively. There were no clear correlations between these gene mutations and the disease-suppressing effect or progression-free survival. Overall, there were many cases showing a decrease in mutations after LEN treatment. Integrating the reduction of CTNNB1 and TP53 genetic mutations increased the potential for disease suppression. CONCLUSION This study suggests that analysis of cfDNA in advanced HCC patients may be useful for identifying LEN responders and determining therapeutic efficacy. Furthermore, it has potential for selecting responders for other molecular-targeted drugs.
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Affiliation(s)
- Mio Tsuruoka
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan,
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoaki Iwata
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akitoshi Sano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kosuke Sato
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masazumi Onuki
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Satoko Sawahashi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Thomas JA, Kendall BJ, El-Serag HB, Thrift AP, Macdonald GA. Hepatocellular and extrahepatic cancer risk in people with non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol 2024; 9:159-169. [PMID: 38215780 DOI: 10.1016/s2468-1253(23)00275-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 08/07/2023] [Accepted: 08/07/2023] [Indexed: 01/14/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Much of the recognised health-care burden occurs in the minority of people with NAFLD who progress towards cirrhosis and require specialist follow-up, including risk stratification and hepatocellular carcinoma surveillance. NAFLD is projected to become the leading global cause of cirrhosis and hepatocellular carcinoma, but the frequency of non-cirrhotic hepatocellular carcinoma provides a challenge to existing surveillance strategies. Deaths from extrahepatic cancers far exceed those from hepatocellular carcinoma in NAFLD. Unlike hepatocellular carcinoma, the increased extrahepatic cancer risk in NAFLD is not dependent on liver fibrosis stage. Given that almost 30% of the world's adult population has NAFLD, extrahepatic cancer could represent a substantial health and economic issue. In this Review, we discuss current knowledge and controversies regarding hepatocellular carcinoma risk stratification and surveillance practices in people with NAFLD. We also assess the associations of extrahepatic cancers with NAFLD and their relevance both in the clinic and the wider community.
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Affiliation(s)
- James A Thomas
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia.
| | - Bradley J Kendall
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
| | - Aaron P Thrift
- Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Graeme A Macdonald
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia
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Tsoneva DK, Ivanov MN, Vinciguerra M. Liquid Liver Biopsy for Disease Diagnosis and Prognosis. J Clin Transl Hepatol 2023; 11:1520-1541. [PMID: 38161500 PMCID: PMC10752811 DOI: 10.14218/jcth.2023.00040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 05/24/2023] [Accepted: 06/07/2023] [Indexed: 01/03/2024] Open
Abstract
Liver diseases are a major burden worldwide, the scope of which is expected to further grow in the upcoming years. Clinically relevant liver dysfunction-related blood markers such as alanine aminotransferase and aspartate aminotransferase have limited accuracy. Nowadays, liver biopsy remains the gold standard for several liver-related pathologies, posing a risk of complication due to its invasive nature. Liquid biopsy is a minimally invasive approach, which has shown substantial potential in the diagnosis, prognosis, and monitoring of liver diseases by detecting disease-associated particles such as proteins and RNA molecules in biological fluids. Histones are the core components of the nucleosomes, regulating essential cellular processes, including gene expression and DNA repair. Following cell death or activation of immune cells, histones are released in the extracellular space and can be detected in circulation. Histones are stable in circulation, have a long half-life, and retain their post-translational modifications. Here, we provide an overview of the current research on histone-mediated liquid biopsy methods for liver diseases, with a focus on the most common detection methods.
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Affiliation(s)
- Desislava K. Tsoneva
- Department of Medical Genetics, Medical University of Varna, Varna, Bulgaria
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
| | - Martin N. Ivanov
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
- Department of Anatomy and Cell Biology, Research Institute, Medical University of Varna, Varna, Bulgaria
| | - Manlio Vinciguerra
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
- Faculty of Health, Liverpool John Moores University, Liverpool, United Kingdom
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Xu Q, Feng M, Ren Y, Liu X, Gao H, Li Z, Su X, Wang Q, Wang Y. From NAFLD to HCC: Advances in noninvasive diagnosis. Biomed Pharmacother 2023; 165:115028. [PMID: 37331252 DOI: 10.1016/j.biopha.2023.115028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/10/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has gradually become one of the major liver health problems in the world. The dynamic course of the disease goes through steatosis, inflammation, fibrosis, and carcinoma. Before progressing to carcinoma, timely and effective intervention will make the condition better, which highlights the importance of early diagnosis. With the further study of the biological mechanism in the pathogenesis and progression of NAFLD, some potential biomarkers have been discovered, and the possibility of their clinical application is gradually being discussed. At the same time, the progress of imaging technology and the emergence of new materials and methods also provide more possibilities for the diagnosis of NAFLD. This article reviews the diagnostic markers and advanced diagnostic methods of NAFLD in recent years.
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Affiliation(s)
- Qinchen Xu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Maoxiao Feng
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China
| | - Yidan Ren
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Xiaoyan Liu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China
| | - Huiru Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Zigan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Xin Su
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Qin Wang
- Department of Anesthesiology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan 250012, China.
| | - Yunshan Wang
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China.
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Wu Y, Wang X, Zhang M, Wu D. Molecular Biomarkers and Recent Liquid Biopsy Testing Progress: A Review of the Application of Biosensors for the Diagnosis of Gliomas. Molecules 2023; 28:5660. [PMID: 37570630 PMCID: PMC10419986 DOI: 10.3390/molecules28155660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/19/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Gliomas are the most common primary central nervous system tumors, with a high mortality rate. Early and accurate diagnosis of gliomas is critical for successful treatment. Biosensors are significant in the detection of molecular biomarkers because they are simple to use, portable, and capable of real-time analysis. This review discusses several important molecular biomarkers as well as various biosensors designed for glioma diagnosis, such as electrochemical biosensors and optical biosensors. We present our perspectives on the existing challenges and hope that this review can promote the improvement of biosensors.
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Affiliation(s)
- Yuanbin Wu
- Department of Emergency Medicine, The Seventh Medical Center, Chinese PLA General Hospital, Beijing 100700, China;
| | - Xuning Wang
- Department of General Surgery, The Air Force Hospital of Northern Theater PLA, Shenyang 110042, China
| | - Meng Zhang
- Department of Neurosurgery, The Second Hospital of Southern Theater of Chinese Navy, Sanya 572000, China
| | - Dongdong Wu
- Department of Neurosurgery, The First Medical Centre, Chinese PLA General Hospital, Beijing 100853, China
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11
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Li H, Liu H, Yan LJ, Ding ZN, Zhang X, Pan GQ, Han CL, Tian BW, Tan SY, Dong ZR, Wang DX, Yan YC, Li T. Performance of GALAD score and serum biomarkers for detecting NAFLD-related HCC: a systematic review and network meta-analysis. Expert Rev Gastroenterol Hepatol 2023; 17:1159-1167. [PMID: 37929312 DOI: 10.1080/17474124.2023.2279175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
INTRODUCTION The incidence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing globally. We aimed to assess the performance of alpha-fetoprotein (AFP), AFP-L3, des-gamma-carboxy prothrombin (DCP), and GALAD score in detecting NAFLD-related HCC. METHODS We searched the relevant literature in PubMed, Embase and Cochrane. Conventional and network meta-analyses were performed for sensitivity, specificity, Youden index (YI), and the area under the summary receiver operator characteristic curve (AUC). RESULTS Fifteen studies involving 2031 NAFLD participants were included in this meta-analysis. When detecting early-stage NAFLD-related HCC, GALAD score and DCP process excellent performance. The sensitivity and AUC of DCP (0.60, 0.74, respectively) were higher than AFP (0.34, 0.59, respectively). The network meta-analysis showed that DCP and GALAD score had similar performance. In detecting all-stage NAFLD-related HCC, GALAD score (sensitivity = 0.87; YI = 0.77) performed better than AFP (sensitivity = 0.56; YI = 0.50), AFP-L3 (sensitivity = 0.39; YI = 0.36) and DCP (sensitivity = 0.73; YI = 0.62). Network meta-analysis obtained consistent results with conventional meta-analysis. CONCLUSIONS Due to the lower cost-effectiveness, DCP was more suitable for detecting early NAFLD-related HCC. AFP could be used in detecting all-stage NAFLD-related HCC.
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Affiliation(s)
- Han Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Guo-Qiang Pan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Bao-Wen Tian
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Si-Yu Tan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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Li JJ, Lv Y, Ji H. Diagnostic performance of circulating tumor DNA as a minimally invasive biomarker for hepatocellular carcinoma: a systematic review and meta-analysis. PeerJ 2022; 10:e14303. [PMID: 36348665 PMCID: PMC9637356 DOI: 10.7717/peerj.14303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 10/05/2022] [Indexed: 11/05/2022] Open
Abstract
Purpose This study aimed to assess the diagnostic performance of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC). Materials and Methods We enrolled all relevant studies published up to 5 January 2022. Three primary subgroups were investigated: qualitative or quantitative ctDNA analyses, combined alpha-fetoprotein (AFP), and ctDNA assay. In addition to the three primary subgroups, we also evaluated the diagnostic value of methylated SEPTIN9 (mSEPT9), which has been studied extensively in the diagnosis of hepatocellular carcinoma. After a search based on four primary databases, we used a bivariate linear mixed model to analyze the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). We also plotted hierarchical summary receiver operating characteristics (HSROC) and utilized lambda as well as the area under the curve (AUC) to create summary receiver operating characteristic (SROC) curves to estimate the diagnostic value of ctDNA. Results A total of 59 qualified articles with 9,766 subjects were incorporated into our meta-analysis. The integrated SEN, SPE, and DOR in the qualitative studies were 0.50 (95% CI [0.43-0.56]), 0.90 (95% CI [0.86-0.93]), and 8.72 (95% CI [6.18-12.32]), respectively, yielding an AUC of 0.78 and lambda of 1.93 (95% CI [1.56-2.33]). For quantitative studies, the corresponding values were 0.69 (95% CI [0.63-0.74]), 0.84 (95% CI [0.77-0.89]), 11.88 (95% CI [7.78-18.12]), 0.81, and 2.32 (95% CI [1.96-2.69]), respectively. Six studies were included to evaluate the SETP9 methylation, which yielded an AUC of 0.86, a SEN of 0.80 (95% CI [0.71-0.87]), and a SPE of 0.77 (95% CI [0.68-0.85]). Likewise, ctDNA concentration yielded an AUC of 0.73, with a SEN of 0.63 (95% CI [0.56-0.70]) and a SPE of 0.86 (95% CI [0.74-0.93]). AFP combined with ctDNA assay resulted in an AUC of 0.89, with a SEN of 0.82 (95% CI [0.77-0.86]) and a SPE of 0.84 (95% CI [0.76-0.90]). Conclusion This study shows that circulating tumor DNA, particularly mSEPT9, shows promising diagnostic potential in HCC; however, it is not enough to diagnose HCC independently, and ctDNA combined with conventional assays such as AFP can effectively improve diagnostic performance.
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Affiliation(s)
- Jia Jie Li
- Hepatobiliary Pancreatic Department, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yanqing Lv
- Department of Hepatobiliary and Pancreatic Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Huifan Ji
- Department of Hepatobiliary and Pancreatic Medicine, The First Hospital of Jilin University, Changchun, Jilin, China
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Ueno M, Takeda H, Takai A, Seno H. Risk factors and diagnostic biomarkers for nonalcoholic fatty liver disease-associated hepatocellular carcinoma: Current evidence and future perspectives. World J Gastroenterol 2022; 28:3410-3421. [PMID: 36158261 PMCID: PMC9346451 DOI: 10.3748/wjg.v28.i27.3410] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/24/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
High rates of excessive calorie intake diets and sedentary lifestyles have led to a global increase in nonalcoholic fatty liver disease (NAFLD). As a result, this condition has recently become one of the leading causes of hepatocellular carcinoma (HCC). Furthermore, the incidence of NAFLD-associated HCC (NAFLD-HCC) is expected to increase in the near future. Advanced liver fibrosis is the most common risk factor for NAFLD-HCC. However, up to 50% of NAFLD-HCC cases develop without underlying liver cirrhosis. Epidemiological studies have revealed many other risk factors for this condition; including diabetes, other metabolic traits, obesity, old age, male sex, Hispanic ethnicity, mild alcohol intake, and elevated liver enzymes. Specific gene variants, such as single-nucleotide polymorphisms of patatin-like phospholipase domain 3, transmembrane 6 superfamily member 2, and membrane-bound O-acyl-transferase domain-containing 7, are also associated with an increased risk of HCC in patients with NAFLD. This clinical and genetic information should be interpreted together for accurate risk prediction. Alpha-fetoprotein (AFP) is the only biomarker currently recommended for HCC screening. However, it is not sufficiently sensitive in addressing this diagnostic challenge. The GALAD score can be calculated based on sex, age, lectin-bound AFP, AFP, and des-carboxyprothrombin and is reported to show better diagnostic performance for HCC. In addition, emerging studies on genetic and epigenetic biomarkers have also yielded promising diagnostic potential. However, further research is needed to establish an effective surveillance program for the early diagnosis of NAFLD-HCC.
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Affiliation(s)
- Masayuki Ueno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
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14
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Serum TERT C228T is an important predictor of non-viral liver cancer with fatty liver disease. Hepatol Int 2022; 16:412-422. [PMID: 35306637 PMCID: PMC9013341 DOI: 10.1007/s12072-022-10313-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 12/05/2021] [Indexed: 11/05/2022]
Abstract
Background Molecular therapies and precision medicine are expected to be developed for liver cancer based on the diagnosis of DNA somatic alterations. However, it remains unclear whether TERT promoter mutation (TERT C228T) in serum cfDNA is useful for the diagnosis of liver cancer with non-viral fatty liver disease (FLD). Methods This retrospective cohort study examined 258 Japanese patients who had a confirmed diagnosis of primary liver cancer. We investigated the factors associated with TERT C228T and abnormal levels of liver cancer-specific tumor markers (AFP and PIVKAII) in serum samples. Results Multivariate analysis identified the etiology of FLD, vascular invasion, and non-cirrhosis as determinants of TERT C228T-positive liver cancer. Rates of positive TERT C228T in FLD were significantly higher than those of HBV and HCV. Conversely, rates of abnormal AFP in FLD were significantly lower than those of HBV and HCV. Viral suppression of HBV/HCV and alcohol intake did not affect TERT C228T, but AFP was significantly reduced by viral suppression. The rates of positive TERT C228T were significantly lower in HCV patients with viral clearance than those of FLD patients. Conclusion Our results highlight the importance of serum TERT C228T for the detection of non-viral FLD-related liver cancer. TERT C228T is a tumor marker that might not be influenced by inflammation. Supplementary Information The online version contains supplementary material available at 10.1007/s12072-022-10313-y.
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15
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Hirata M, Fujita K, Fujihara S, Mizuo T, Nakabayashi R, Kono T, Namima D, Fujita N, Yamana H, Kamada H, Tani J, Kobara H, Tsutsui K, Matsuda Y, Ono M, Masaki T. Telomerase Reverse Transcriptase Promoter Mutations in Human Hepatobiliary, Pancreatic and Gastrointestinal Cancer Cell Lines. In Vivo 2022; 36:94-102. [PMID: 34972704 DOI: 10.21873/invivo.12680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 09/27/2021] [Accepted: 10/29/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIM The promoter region of the telomerase reverse transcriptase (TERT) gene is a regulatory element capable of affecting TERT expression, telomerase activity, and telomerase length. Mutations within the TERT promoter region are the most common mutations in many cancers. In this study, we characterized the TERT promoter mutation status in hepatobiliary, pancreatic, and gastrointestinal cancer cell lines. MATERIALS AND METHODS TERT promoter mutation status was assessed by digital PCR in 12 liver cancer, 5 cholangiocarcinoma (CCA), 12 pancreatic cancer, 17 gastrointestinal cancer, and 3 healthy control cell lines. RESULTS The C228T promoter mutation was detected in 9 liver cancer lines, and the C250T TERT mutation was detected in 1 oesophageal squamous cell carcinoma line. CONCLUSION The C228T promoter mutation is specific to liver cancer cell lines among various gastrointestinal cancer cell lines. These data will contribute to future research on the tumorigenic mechanisms and clinical use of digital PCR to detect mutations.
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Affiliation(s)
- Masahiro Hirata
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Takaaki Mizuo
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Ryota Nakabayashi
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Toshiaki Kono
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Daisuke Namima
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Naoki Fujita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hiroki Yamana
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hideki Kamada
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Kunihiko Tsutsui
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Yoko Matsuda
- Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan;
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Rios RS, Zheng KI, Zheng MH. Non-alcoholic steatohepatitis and risk of hepatocellular carcinoma. Chin Med J (Engl) 2021; 134:2911-2921. [PMID: 34855640 PMCID: PMC8710331 DOI: 10.1097/cm9.0000000000001888] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Indexed: 12/18/2022] Open
Abstract
ABSTRACT The emergence of non-alcoholic fatty liver disease (NAFLD) as the leading chronic liver disease worldwide raises some concerns. In particular, NAFLD is closely tied to sedentary lifestyle habits and associated with other metabolic diseases, such as obesity and diabetes. At the end of the disease spectrum, non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma (HCC), representing a serious health problem to modern society. Recently, an increasing number of HCC cases originating from this progressive disease spectrum have been identified, with different levels of severity and complications. Updating the current guidelines by placing a bigger focus on this emerging cause and highlighting some of its unique features is necessary. Since, the drivers of the disease are complex and multifactorial, in order to improve future outcomes, having a better understanding of NASH progression into HCC may be helpful. The risks that can promote disease progression and currently available management strategies employed to monitor and treat NASH-related HCC make up the bulk of this review.
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Affiliation(s)
- Rafael S. Rios
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Kenneth I. Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang 325000, China
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17
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Muraoka M, Maekawa S, Katoh R, Komiyama Y, Nakakuki N, Takada H, Matsuda S, Suzuki Y, Sato M, Tatsumi A, Miura M, Amemiya F, Shindo H, Takano S, Fukasawa M, Yamauchi K, Yamaguchi T, Nakayama Y, Inoue T, Enomoto N. Usefulness of Cell-Free Human Telomerase Reverse Transcriptase Mutant DNA Quantification in Blood for Predicting Hepatocellular Carcinoma Treatment Efficacy. Hepatol Commun 2021; 5:1927-1938. [PMID: 34558819 PMCID: PMC8557313 DOI: 10.1002/hep4.1762] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/28/2021] [Accepted: 05/16/2021] [Indexed: 12/26/2022] Open
Abstract
Although the usefulness of liquid biopsy as a biomarker in the treatment of hepatocellular carcinoma (HCC) has been suggested, its usefulness in transcatheter arterial chemoembolization (TACE) or tyrosine kinase inhibitor (TKI) therapies has not been reported in detail. In this study, we investigated the clinical value of a cell-free (cf)DNA quantification system targeting the human telomerase reverse transcriptase (hTERT) promoter mutation in advanced HCC treatment. Plasma from 67 patients with advanced HCC, treated with TACE and TKI, was used for extraction of cfDNA. We defined cfDNA with the hTERT promoter C228T mutation as circulating mutant DNA (mutant DNA) and without the mutation as circulating wild-type DNA (wild-type DNA). We analyzed the changes in mutant and wild-type DNA levels during HCC treatment and examined the relationship between changes in the cfDNA level and the clinical course. Mutant DNA was detected in 73.1% (49/67) of the patients during HCC treatment. In univariate analysis, factors associated with detection of mutant DNA before treatment were the intrahepatic maximum tumor diameter (P = 0.015) and protein induced by vitamin K absence (PIVKAII) (P = 0.006). The degree of mutant DNA change after TACE was significantly correlated with tumor volume (P < 0.001), reflecting the treated tumor volume. Responders with peak cfDNA levels within 1 week of TKI initiation had significantly better progression-free survival than nonresponders (P = 0.004). Conclusion: Changes in blood hTERT promoter mutant DNA levels during TACE or TKI treatment indirectly reflect the amount of HCCs and are useful for predicting long-term treatment responses.
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Affiliation(s)
- Masaru Muraoka
- First Department of Internal MedicineFaculty of MedicineUniversity of YamanashiChuoJapan
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Ge Z, Helmijr JCA, Jansen MPHM, Boor PPC, Noordam L, Peppelenbosch M, Kwekkeboom J, Kraan J, Sprengers D. Detection of oncogenic mutations in paired circulating tumor DNA and circulating tumor cells in patients with hepatocellular carcinoma. Transl Oncol 2021; 14:101073. [PMID: 33915518 PMCID: PMC8100622 DOI: 10.1016/j.tranon.2021.101073] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/17/2021] [Accepted: 03/08/2021] [Indexed: 12/24/2022] Open
Abstract
In paired analysis CTCs were detected in 27% and ctDNA in 77% of HCC patients. The TERT promoter mutation C228T was present in all patients with one or more ctDNA mutations, or detectable CTCs. CtDNA (or TERT C228T) positivity was associated with macrovascular invasion and poor survival of advanced HCC patients. Background and aims Circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) may be used for diagnostic or prognostic purposes in patients with hepatocellular carcinoma (HCC). We aim to determine whether CTCs or ctDNA are suitable to determine oncogenic mutations in HCC patients. Methods Twenty-six mostly advanced HCC patients were enrolled. 30 mL peripheral blood from each patient was obtained. CellSearch system was used for CTC detection. A sequencing panel covering 14 cancer-relevant genes was used to identify oncogenic mutations. TERT promoter C228T and C250T mutations were determined by droplet digital PCR. Results CTCs were detected in 27% (7/26) of subjects but at low numbers (median: 2 cells, range: 1–15 cells) and ctDNA in 77% (20/26) of patients. Mutations in ctDNA were identified in several genes: TERT promoter C228T (77%, 20/26), TP53 (23%, 6/26), CTNNB1 (12%, 3/26), PIK3CA (12%, 3/26) and NRAS (4%, 1/26). The TERT C228T mutation was present in all patients with one or more ctDNA mutations, or detectable CTCs. The TERT C228T and TP53 mutations detected in ctDNA were present at higher levels in matched primary HCC tumor tissue. The maximal variant allele frequency (VAF) of ctDNA was linearly correlated with largest tumor size and AFP level (Log10). CtDNA (or TERT C228T) positivity was associated with macrovascular invasion, and positivity of ctDNA (or TERT C228T) or CTCs (≥ 2) correlated with poor patient survival. Conclusions Oncogenic mutations could be detected in ctDNA from advanced HCC patients. CtDNA analysis may serve as a promising liquid biopsy to identify druggable mutations.
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Affiliation(s)
- Zhouhong Ge
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Jean C A Helmijr
- Departments of Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Maurice P H M Jansen
- Departments of Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Patrick P C Boor
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Lisanne Noordam
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Maikel Peppelenbosch
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Jaap Kwekkeboom
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Jaco Kraan
- Departments of Medical Oncology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Dave Sprengers
- Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands.
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Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk. Int J Mol Sci 2021; 22:ijms22094459. [PMID: 33923295 PMCID: PMC8123173 DOI: 10.3390/ijms22094459] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 02/07/2023] Open
Abstract
NAFLD (non-alcoholic fatty liver disease) is a widespread liver disease that is often linked with other life-threatening ailments (metabolic syndrome, insulin resistance, diabetes, cardiovascular disease, atherosclerosis, obesity, and others) and canprogress to more severe forms, such as NASH (non-alcoholic steatohepatitis), cirrhosis, and HCC (hepatocellular carcinoma). In this review, we summarized and analyzed data about single nucleotide polymorphism sites, identified in genes related to NAFLD development and progression. Additionally, the causative role of mitochondrial mutations and mitophagy malfunctions in NAFLD is discussed. The role of mitochondria-related metabolites of the urea cycle as a new non-invasive NAFLD biomarker is discussed. While mitochondria DNA mutations and SNPs (single nucleotide polymorphisms) canbe used as effective diagnostic markers and target for treatments, age and ethnic specificity should be taken into account.
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20
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Lewin J, Kottwitz D, Aoyama J, deVos T, Garces J, Hasinger O, Kasielke S, Knaust F, Rathi P, Rausch S, Weiss G, Zipprich A, Mena E, Fong TL. Plasma cell free DNA methylation markers for hepatocellular carcinoma surveillance in patients with cirrhosis: a case control study. BMC Gastroenterol 2021; 21:136. [PMID: 33765926 PMCID: PMC7995734 DOI: 10.1186/s12876-021-01714-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 03/09/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis, primarily due to failed early detection. HCC screening is recommended among individuals with cirrhosis using biannual abdominal ultrasound, for earlier tumor detection, administration of curative treatment, and improved survival. Surveillance by imaging with or without biomarkers such as alpha-fetoprotein (AFP) remains suboptimal for early stage HCC detection. Here we report on the development and assessment of methylation biomarkers from liquid biopsies for HCC surveillance in cirrhotic patients. METHODS DNA methylation markers including the HCCBloodTest (Epigenomics AG) and a DNA-methylation panel established by next generation sequencing (NGS) were assessed using a training/testing design. The NGS panel algorithm was established in a training study (41 HCC patients; 46 cirrhotic non-HCC controls). For testing, plasma samples were obtained from cirrhotic patients (Child class A or B) with (60) or without (103) early stage HCC (BCLC stage 0, A, B). The assays were then tested using blinded sample sets and analyzed by preset algorithms. RESULTS The HCCBloodTest and the NGS panel exhibited 76.7% and 57% sensitivities at 64.1% and 97% specificity, respectively. In a post-hoc analysis, a combination of the NGS panel with AFP (20 ng/mL) achieved 68% sensitivity at 97% specificity (AUC = 0.9). CONCLUSIONS Methylation biomarkers in cell free plasma DNA provide a new alternative for HCC surveillance. Multiomic panels comprising DNA methylation markers with other biological markers, such as AFP, provide an option to further increase the overall clinical performance of surveillance via minimally invasive blood samples. TRIAL REGISTRATION Test set study-ClinicalTrials.gov (NCT03804593) January 11, 2019, retrospectively registered.
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Affiliation(s)
- Jörn Lewin
- Epigenomics AG, Geneststr. 5, 10829, Berlin, Germany
| | | | | | - Theo deVos
- Epigenomics Inc., 11055 Flintkote Ave, Suite A, San Diego, CA, 92121, USA.
| | - Jorge Garces
- Epigenomics AG, Geneststr. 5, 10829, Berlin, Germany
| | | | | | | | - Preeti Rathi
- Epigenomics AG, Geneststr. 5, 10829, Berlin, Germany
| | | | - Gunter Weiss
- Epigenomics AG, Geneststr. 5, 10829, Berlin, Germany
| | - Alexander Zipprich
- Universitätsklinik und Poliklinik für Innere Medizin I, UKH Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany
| | - Edward Mena
- California Liver Research Institute, 301 S. Fair Oaks Avenue, Suite 409, Pasadena, CA, 91105, USA
| | - Tse-Ling Fong
- Keck School of Medicine, USC, 1510 San Pablo Street, 2/F, Los Angeles, CA, 90033, USA
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