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Zamani K, Rostami P, Darehbagh RR, Afraie M, Moradi Y. Hepatitis B and C virus infection and risk of multiple myeloma: a systematic review and meta-analysis. BMC Cancer 2025; 25:998. [PMID: 40468263 PMCID: PMC12135261 DOI: 10.1186/s12885-025-14420-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Accepted: 05/30/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND Multiple myeloma (MM) is a clonal proliferative disorder of plasma cells with limited curative options. Hepatitis B (HBV) and hepatitis C (HCV) viruses have been implicated in the development of various hematological malignancies, but their association with MM remains unclear. This systematic review and meta-analysis aimed to investigate the risk of MM in individuals with HBV and HCV infections. METHODS A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, Embase, and additional sources for cohort and case-control studies published between January 1990 and January 2025. The relative risk (RR) of developing MM in individuals with HBV and HCV infections was pooled using a random-effects model. Subgroup analyses were performed based on age, geographic region, and diagnostic method. The Newcastle-Ottawa Scale (NOS) was used to assess study quality. Statistical heterogeneity was evaluated using the I² statistic, and publication bias was assessed using Egger's test. RESULTS Seventeen studies, comprising 1 cohort and 16 case-control studies, were included. Nine studies examined the association between HBV and MM, yielding a pooled RR of 1.25 (95% CI: 0.99-1.58) with moderate heterogeneity (I² = 56.52%). Fifteen studies evaluated the association between HCV and MM, with a pooled RR of 1.84 (95% CI: 1.27-2.67), indicating a higher risk in HCV-infected individuals. Subgroup analysis revealed a stronger association in European populations for both HBV (RR: 1.67, 95% CI: 1.05-2.66) and HCV (RR: 2.27, 95% CI: 1.21-4.25). No significant publication bias was detected for either HBV or HCV analyses. CONCLUSION HBV and HCV infections are associated with an increased risk of developing multiple myeloma, with HCV demonstrating a stronger association. These findings highlight the importance of screening and monitoring patients with chronic hepatitis for potential hematological malignancies, especially in high-risk regions.
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Affiliation(s)
- Kamran Zamani
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Poorya Rostami
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | | | - Maryam Afraie
- Department of Epidemiology and Biostatistics, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
| | - Yousef Moradi
- Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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2
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Weniger MA, Seifert M, Küppers R. B Cell Differentiation and the Origin and Pathogenesis of Human B Cell Lymphomas. Methods Mol Biol 2025; 2865:1-30. [PMID: 39424718 DOI: 10.1007/978-1-0716-4188-0_1] [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] [Indexed: 10/21/2024]
Abstract
Immunoglobulin (IG) gene remodeling by V(D)J recombination plays a central role in the generation of normal B cells, and somatic hypermutation and class switching of IG genes are key processes during antigen-driven B cell differentiation in the germinal center reaction. However, errors of these processes are involved in the development of B cell lymphomas. IG locus-associated translocations of proto-oncogenes are a hallmark of many B cell malignancies. Additional transforming events include inactivating mutations in various tumor suppressor genes and also latent infection of B cells with viruses, such as Epstein-Barr virus. Most B cell lymphomas require B cell antigen receptor expression, and in several instances chronic antigenic stimulation plays a role in lymphoma development and/or sustaining tumor growth. Often, survival and proliferation signals provided by other cells in the microenvironment are a further critical factor in lymphoma development and pathophysiology. Most B cell malignancies derive from germinal center B cells, most likely due to the high proliferative activity of these B cells and aberrant mutations caused by their naturally active mutagenic processes.
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Affiliation(s)
- Marc A Weniger
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany
| | - Marc Seifert
- Department of Haematology, Oncology and Clinical Immunology, Heinrich Heine University, Medical School, Düsseldorf, Germany
| | - Ralf Küppers
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany.
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3
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Šenigl F, Soikkeli AI, Prost S, Schatz DG, Slavková M, Hejnar J, Alinikula J. The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity. Tumour Virus Res 2024; 18:200293. [PMID: 39490533 PMCID: PMC11564006 DOI: 10.1016/j.tvr.2024.200293] [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: 04/22/2024] [Revised: 09/19/2024] [Accepted: 10/25/2024] [Indexed: 11/05/2024] Open
Abstract
Simian virus 40 (SV40) is a monkey virus with tumorigenic potential in rodents and is associated with several types of human cancers, including lymphomas. A related Merkel cell polyomavirus causes carcinoma in humans by expressing truncated large tumor antigen (LT), with truncations caused by APOBEC family of cytidine deaminase-induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID could cause mutations in SV40 LT. We demonstrate that the SV40 enhancer has strong somatic hypermutation targeting activity in several cell types and that AID-induced mutations accumulate in SV40 LT in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target somatic hypermutation to LT is a potential source of LT truncation events that could contribute to tumorigenesis in various cell types, thereby linking SV40 infection with malignant development through a novel mutagenic pathway.
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Affiliation(s)
- Filip Šenigl
- Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, 14220, Czech Republic.
| | - Anni I Soikkeli
- Institute of Biomedicine, University of Turku, Turku, 20520, Finland; Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland
| | - Salomé Prost
- Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, 14220, Czech Republic
| | - David G Schatz
- Department of Immunobiology, Yale School of Medicine, New Haven.CT, 06520-8011, USA
| | - Martina Slavková
- Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, 14220, Czech Republic
| | - Jiří Hejnar
- Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, 14220, Czech Republic
| | - Jukka Alinikula
- Institute of Biomedicine, University of Turku, Turku, 20520, Finland.
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4
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Hung JH, Teng CF, Hung HC, Chen YL, Chen PJ, Ho CL, Chuang CH, Huang W. Genomic instabilities in hepatocellular carcinoma: biomarkers and application in immunotherapies. Ann Hepatol 2024; 29:101546. [PMID: 39147130 DOI: 10.1016/j.aohep.2024.101546] [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: 01/26/2024] [Revised: 05/16/2024] [Accepted: 06/18/2024] [Indexed: 08/17/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. For patients with advanced HCC, liver function decompensation often occurs, which leads to poor tolerance to chemotherapies and other aggressive treatments. Therefore, it remains critical to develop effective therapeutic strategies for HCC. Etiological factors for HCC are complex and multifaceted, including hepatitis virus infection, alcohol, drug abuse, chronic metabolic abnormalities, and others. Thus, HCC has been categorized as a "genomically unstable" cancer due to the typical manifestation of chromosome breakage and aneuploidy, and oxidative DNA damage. In recent years, immunotherapy has provided a new option for cancer treatments, and the degree of genomic instability positively correlates with immunotherapy efficacies. This article reviews the endogenous and exogenous causes that affect the genomic stability of liver cells; it also updates the current biomarkers and their detection methods for genomic instabilities and relevant applications in cancer immunotherapies. Including genomic instability biomarkers in consideration of cancer treatment options shall increase the patients' well-being.
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Affiliation(s)
- Jui-Hsiang Hung
- Department of Biotechnology, Chia Nan University of Pharmacy & Science, Tainan, Taiwan
| | - Chiao-Feng Teng
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan; Program for Cancer Biology and Drug Development, China Medical University, Taichung, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Hsu-Chin Hung
- Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Lin Chen
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Pin-Jun Chen
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Liang Ho
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Cheng-Hsiang Chuang
- Department of Life Science, College of Life Sciences and Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Wenya Huang
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan; Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Infectious Diseases and Signal Transduction, National Cheng Kung University, Tainan, Taiwan..
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5
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Ivanova VS, Menter T, Zaino J, Mertz KD, Hamelin B, Dirnhofer S, Kloboves-Prevodnik V, Tzankov A, Gašljević G. The Genetic Landscape of Primary Breast Marginal Zone Lymphoma Identifies a Mutational-driven Disease With Similarities to Ocular Adnexal Lymphoma. Am J Surg Pathol 2024; 48:1259-1269. [PMID: 38864239 DOI: 10.1097/pas.0000000000002257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2024]
Abstract
Extranodal marginal zone lymphomas (eMZL) can occur in any organ and site of the body. Recent research has shown that they differ from organ to organ in terms of their mutational profile. In this study, we investigated a cohort of primary breast marginal zone lymphomas (PBMZL) to get a better insight into their morphologic and molecular profile. A cohort of 15 cases (14 female and 1 male) was characterized by immunohistochemistry (IHC) for 19 markers, fluorescence in situ hybridization (FISH), and high throughput sequencing (HTS) using a lymphoma panel comprising 172 genes. In addition, PCR for the specific detection of Borrelia spp. and metagenomics whole genome sequencing were performed for infectious agent profiling. Follicular colonization was observed in most cases, while lymphoepithelial lesions, though seen in many cases, were not striking. All 15 cases were negative for CD5, CD11c, and CD21 and positive for BCL2 and pan B-cell markers. There were no cases with BCL2 , BCL10 , IRF4 , MALT1 , or MYC translocation; only 1 had a BCL6 rearrangement. HTS highlighted TNFAIP3 (n=4), KMT2D (n=2), and SPEN (n=2) as the most frequently mutated genes. There were no Borrelia spp. , and no other pathogens detected in our cohort. One patient had a clinical history of erythema chronicum migrans affecting the same breast. PBMZL is a mutation-driven disease rather than fusion-driven. It exhibits mutations in genes encoding components affecting the NF-κB pathway, chromatin modifier-encoding genes, and NOTCH pathway-related genes. Its mutational profile shares similarities with ocular adnexal and nodal MZL.
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MESH Headings
- Humans
- Female
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/microbiology
- Lymphoma, B-Cell, Marginal Zone/pathology
- Middle Aged
- Mutation
- Male
- Aged
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/analysis
- Adult
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Eye Neoplasms/genetics
- Eye Neoplasms/pathology
- Eye Neoplasms/microbiology
- DNA Mutational Analysis
- Aged, 80 and over
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Genetic Predisposition to Disease
- High-Throughput Nucleotide Sequencing
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Affiliation(s)
- Vanesa-Sindi Ivanova
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel
| | - Thomas Menter
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel
| | - Joel Zaino
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel
| | - Kirsten D Mertz
- Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland
| | - Baptiste Hamelin
- Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland
| | - Stefan Dirnhofer
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel
| | | | - Alexandar Tzankov
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel
| | - Gorana Gašljević
- Department of Pathology, Institute of Oncology Ljubljana, Ljubljana
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
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6
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Tani J, Masaki T, Oura K, Tadokoro T, Morishita A, Kobara H. Extrahepatic Cancer Risk in Patients with Hepatitis C Virus Infection Treated with Direct-Acting Antivirals. Microorganisms 2024; 12:1926. [PMID: 39338599 PMCID: PMC11434491 DOI: 10.3390/microorganisms12091926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
Chronic hepatitis C virus (HCV) infection is associated with an increased risk of extrahepatic cancers, particularly non-Hodgkin lymphoma. The introduction of direct-acting antivirals (DAAs) has revolutionized HCV therapy, resulting in high cure rates. However, concerns have been raised about potential effects on cancer risk. This review summarizes the current evidence on extrahepatic cancer risk in HCV-infected patients treated with DAAs. We examined epidemiologic data on HCV-associated extrahepatic cancers and explored potential mechanisms linking HCV to carcinogenesis outside the liver. Studies evaluating cancer outcomes after DAA therapy were critically reviewed while considering methodological challenges. While some studies suggested a reduced risk of extrahepatic cancers after DAA therapy, others showed no significant change. Limitations included short follow-up periods and confounding variables. Immunological changes following rapid HCV clearance may have complex effects on cancer risk. Long-term prospective studies and mechanistic investigations are needed to fully elucidate the relationship between DAA therapy and extrahepatic cancer risk in HCV patients. Clinicians should remain vigilant for extrahepatic malignancies in this population.
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Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Tsutomu Masaki
- Kagawa Saiseikai Hospital, Takamatsu 761-8076, Kagawa, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Takamatsu 761-0793, Kagawa, Japan
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7
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Zhang W, Zeng M, Li Y, Yu L. Leveraging oncovirus-derived antigen against the viral malignancies in adoptive cell therapies. Biomark Res 2024; 12:71. [PMID: 39075601 PMCID: PMC11287861 DOI: 10.1186/s40364-024-00617-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/10/2024] [Indexed: 07/31/2024] Open
Abstract
Adoptive cell therapies (ACTs) have revolutionized cancer immunotherapy, prompting exploration into their application against oncoviruses. Oncoviruses such as human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV) contribute significantly (12-25%) to human malignancies through direct or indirect oncogenic mechanisms. These viruses persistently or latently infect cells, disrupt cellular homeostasis and pathways, challenging current antiviral treatment paradigms. Moreover, viral infections pose additional risks in the setting of long-term cancer therapy and lead to morbidity and mortality. Virally encoded oncoproteins, which are tumor-restricted, immunologically foreign, and even uniformly expressed, represent promising targets for patient-tailored ACTs. This review elucidates the rationale for leveraging viral antigen-specific ACTs in combating viral-associated malignancies. On this basis, ongoing preclinical studies consolidate our understanding of harnessing ACTs against viral malignancies, underscoring their potential to eradicate viruses implicated in cancer progression. Furthermore, we scrutinize the current landscape of clinical trials focusing on virus-specific ACTs and discuss their implications for therapeutic advancement.
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Affiliation(s)
- Wei Zhang
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen, 518060, China
| | - Miao Zeng
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen, 518060, China
| | - Yisheng Li
- Shenzhen Haoshi Biotechnology Co., Ltd, No. 155 Hongtian Road, Xinqiao Street, Bao'an District, Shenzhen, Guangdong, 518125, China
- Haoshi Cell Therapy Institute, Shenzhen University, Shenzhen, China
| | - Li Yu
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518000, China.
- Haoshi Cell Therapy Institute, Shenzhen University, Shenzhen, China.
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8
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Leeman-Neill RJ, Bhagat G, Basu U. AID in non-Hodgkin B-cell lymphomas: The consequences of on- and off-target activity. Adv Immunol 2024; 161:127-164. [PMID: 38763700 DOI: 10.1016/bs.ai.2024.03.005] [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] [Indexed: 05/21/2024]
Abstract
Activation induced cytidine deaminase (AID) is a key element of the adaptive immune system, required for immunoglobulin isotype switching and affinity maturation of B-cells as they undergo the germinal center (GC) reaction in peripheral lymphoid tissue. The inherent DNA damaging activity of this enzyme can also have off-target effects in B-cells, producing lymphomagenic chromosomal translocations that are characteristic features of various classes of non-Hodgkin B-cell lymphoma (B-NHL), and generating oncogenic mutations, so-called aberrant somatic hypermutation (aSHM). Additionally, AID has been found to affect gene expression through demethylation as well as altered interactions between gene regulatory elements. These changes have been most thoroughly studied in B-NHL arising from GC B-cells. Here, we describe the most common classes of GC-derived B-NHL and explore the consequences of on- and off-target AID activity in B and plasma cell neoplasms. The relationships between AID expression, including effects of infection and other exposures/agents, mutagenic activity and lymphoma biology are also discussed.
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Affiliation(s)
- Rebecca J Leeman-Neill
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States; Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States.
| | - Govind Bhagat
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
| | - Uttiya Basu
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
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9
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Zhang Y, Guo W, Zhan Z, Bai O. Carcinogenic mechanisms of virus-associated lymphoma. Front Immunol 2024; 15:1361009. [PMID: 38482011 PMCID: PMC10932979 DOI: 10.3389/fimmu.2024.1361009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 02/12/2024] [Indexed: 04/17/2024] Open
Abstract
The development of lymphoma is a complex multistep process that integrates numerous experimental findings and clinical data that have not yet yielded a definitive explanation. Studies of oncogenic viruses can help to deepen insight into the pathogenesis of lymphoma, and identifying associations between lymphoma and viruses that are established and unidentified should lead to cellular and pharmacologically targeted antiviral strategies for treating malignant lymphoma. This review focuses on the pathogenesis of lymphomas associated with hepatitis B and C, Epstein-Barr, and human immunodeficiency viruses as well as Kaposi sarcoma-associated herpesvirus to clarify the current status of basic information and recent advances in the development of virus-associated lymphomas.
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Affiliation(s)
| | | | | | - Ou Bai
- Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China
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10
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Šenigl F, Soikkeli A, Prost S, Schatz DG, Slavková M, Hejnar J, Alinikula J. The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential oncogenic activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.09.574829. [PMID: 38260396 PMCID: PMC10802419 DOI: 10.1101/2024.01.09.574829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Simian virus 40 (SV40) is a monkey virus associated with several types of human cancers. SV40 is most frequently detected in mesotheliomas, brain and bone tumors and lymphomas, but the mechanism for SV40 tumorigenesis in humans is not clear. SV40 relative Merkel cell polyomavirus (MCPyV) causes Merkel cell carcinoma (MCC) in humans by expressing truncated large tumor antigen (LT) caused by APOBEC cytidine deaminase family enzymes induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation (SHM) and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID-induced mutations could cause truncation of SV40 LT. We demonstrate that the SV40 enhancer has strong SHM targeting activity in several cell types and that AID-induced mutations accumulate to SV40 LT in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target SHM to LT is a potential source of LT truncation events in various cell types that could contribute to carcinogenesis.
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11
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Gaur P, Rajak N, Tiwari A, Kumar P, Garg N. Role of microRNAs in oncogenic viral infection diagnosis and therapeutics. MICRORNA IN HUMAN INFECTIOUS DISEASES 2024:179-200. [DOI: 10.1016/b978-0-323-99661-7.00005-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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12
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Visentini M, Pica A, D'Ippolito G, Sculco E, La Gualana F, Gragnani L, Miglionico M, Mazzaro C, Fiorilli M, Basili S, Martelli M, Di Rocco A, Casato M, Gentile G, Pulsoni A. High prevalence of past hepatitis B virus infection in diffuse large B cell lymphoma: a retrospective study from Italy. Ann Hematol 2023; 102:3457-3463. [PMID: 37650886 PMCID: PMC10640471 DOI: 10.1007/s00277-023-05412-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/09/2023] [Indexed: 09/01/2023]
Abstract
Studies from high endemic areas, mostly China, indicate that surface antigen positive (HBsAgpos) chronic hepatitis B virus (HBV) infection is associated with an increased risk of developing diffuse large B-cell lymphoma (DLBCL), whereas studies in low endemic areas have provided conflicting results. Past infection, serologically defined by negative HBsAg and positive anti-core antibody (HBsAgnegHBcAbpos), has also been suggested to increase the risk of B-cell non-Hodgkin's lymphoma (NHL) in high endemic areas. We retrospectively reviewed unselected clinical records of 253 patients with DLBCL (54% male, aged 60.3 ± 14.6 years at diagnosis) and 694 patients with different types of indolent B-cell NHL (46% male, aged 61.7 ± 12.8 years). Patients were seen at a single center in Italy between 2001 and 2022 and HBV serological status (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb, and HBV DNA) was analyzed through enzyme-linked immunosorbent assays and molecular assays; patients infected with hepatitis C virus or human immunodeficiency virus were excluded. We used an unconditional multiple logistic regression model including as matching variables gender, age at diagnosis, immigrant status, and HBV serological status. Patients with DLBCL had, compared to indolent NHL, a higher prevalence of HBsAgpos active infection (odds ratio (OR) 2.8, 95% confidence interval (95% CI) 1.2-6.3, p = 0.014). Strikingly, patients with DLBCL had also a significantly higher prevalence of past infection (OR 2.4, 95% CI 1.5-4.0, p = 0.0006). Male gender was associated with increased risk of DLBCL independently of the HBV serological status. These findings suggest that both past and active HBV infection may increase the risk of DLBCL in a low endemic area. Our study needs confirmation by studies in areas or populations with different rates of chronic or past HBV infection.
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Affiliation(s)
- Marcella Visentini
- Division of Clinical Immunology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
| | - Andrea Pica
- Division of Clinical Immunology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Giancarlo D'Ippolito
- Division of Clinical Immunology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Eleonora Sculco
- Division of Clinical Immunology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesca La Gualana
- Division of Clinical Immunology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Laura Gragnani
- Department of Translational Research & NTMS, University of Pisa, Pisa, Italy
| | - Marzia Miglionico
- Division of Clinical Immunology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Cesare Mazzaro
- Unit of Clinical of Experimental Onco-Haematology, IRCCS Centro di Riferimento Oncologico (CRO), Aviano, Pordenone, Italy
| | - Massimo Fiorilli
- Division of Clinical Immunology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Stefania Basili
- Division of Clinical Immunology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Maurizio Martelli
- Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Alice Di Rocco
- Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Milvia Casato
- Division of Clinical Immunology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Giuseppe Gentile
- Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessandro Pulsoni
- Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
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13
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Grand RJ. SARS-CoV-2 and the DNA damage response. J Gen Virol 2023; 104:001918. [PMID: 37948194 PMCID: PMC10768691 DOI: 10.1099/jgv.0.001918] [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: 09/01/2023] [Accepted: 10/27/2023] [Indexed: 11/12/2023] Open
Abstract
The recent coronavirus disease 2019 (COVID-19) pandemic was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is characterized by respiratory distress, multiorgan dysfunction and, in some cases, death. The virus is also responsible for post-COVID-19 condition (commonly referred to as 'long COVID'). SARS-CoV-2 is a single-stranded, positive-sense RNA virus with a genome of approximately 30 kb, which encodes 26 proteins. It has been reported to affect multiple pathways in infected cells, resulting, in many cases, in the induction of a 'cytokine storm' and cellular senescence. Perhaps because it is an RNA virus, replicating largely in the cytoplasm, the effect of SARS-Cov-2 on genome stability and DNA damage responses (DDRs) has received relatively little attention. However, it is now becoming clear that the virus causes damage to cellular DNA, as shown by the presence of micronuclei, DNA repair foci and increased comet tails in infected cells. This review considers recent evidence indicating how SARS-CoV-2 causes genome instability, deregulates the cell cycle and targets specific components of DDR pathways. The significance of the virus's ability to cause cellular senescence is also considered, as are the implications of genome instability for patients suffering from long COVID.
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Affiliation(s)
- Roger J. Grand
- Institute for Cancer and Genomic Science, The Medical School, University of Birmingham, Birmingham, UK
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14
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Zhang W, Du F, Wang L, Bai T, Zhou X, Mei H. Hepatitis Virus-associated Non-hodgkin Lymphoma: Pathogenesis and Treatment Strategies. J Clin Transl Hepatol 2023; 11:1256-1266. [PMID: 37577221 PMCID: PMC10412707 DOI: 10.14218/jcth.2022.00079s] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/21/2023] [Accepted: 03/22/2023] [Indexed: 07/03/2023] Open
Abstract
Over the last decade, epidemiological studies have discovered a link between hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). The regression of HCV-associated NHL after HCV eradication is the most compelling proof supporting HCV infection's role in lymphoproliferative diseases. HBV infection was found to significantly enhance the incidence of NHL, according to the epidemiological data. The exact mechanism of HCV leading to NHL has not been fully clarified, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HCV and cytokines; (2) Direct mechanisms: oncogenic effects mediated by intracellular HCV proteins; (3) hit-and-run mechanism: permanent genetic B lymphocytes damage by the transitional entry of HCV. The specific role of HBV in the occurrence of NHL is still unclear, and the research on its mechanism is less extensively explored than HCV, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HBV; (2) Direct mechanisms: oncogenic effects mediated by intracellular HBV DNA. In fact, it is reasonable to consider direct-acting antivirals (DAAs) as first-line therapy for indolent HCV-associated B-NHL patients who do not require immediate chemotherapy. Chemotherapy for NHL is affected by HBV infection and replication. At the same time, chemotherapy can also activate HBV replication. Following recent guidelines, all patients with HBsAg positive/HBV DNA≥2,000 IU/mL should be treated for HBV. The data on epidemiology, interventional studies, and molecular mechanisms of HCV and HBV-associated B-NHL are systematically summarized in this review.
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Affiliation(s)
- Wenjing Zhang
- Department of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fan Du
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Li Wang
- Department of Hematology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tao Bai
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiang Zhou
- Department of Internal Medicine II, Würzburg University Hospital, University of Würzburg, Würzburg, Germany
| | - Heng Mei
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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15
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Hung SH, Yang TH, Cheng YF, Chen CS, Lin HC. Associations of Head and Neck Cancer with Hepatitis B Virus and Hepatitis C Virus Infection. Cancers (Basel) 2023; 15:4510. [PMID: 37760479 PMCID: PMC10526944 DOI: 10.3390/cancers15184510] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/04/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
This case-control study investigates the associations between head and neck cancer (HNC), hepatitis B virus (HBV), and hepatitis C virus (HCV) infection. We included 5603 patients who had received a diagnosis of HNC as cases and 16,809 propensity score matching controls. We employed multivariate logistic regression models to evaluate the association of HNC with HBV and HCV infection after taking sociodemographic characteristics and diabetes, hypertension, hyperlipidemia, HPV infection, tobacco use disorder, and alcohol abuse/alcohol dependence syndrome into considerations. Results show that 7.9% of the total sample had been previously diagnosed with HBV infection, with 9.0% prevalence among cases and 7.6% among controls (p < 0.001). The chi-squared test suggests a significant difference in the prevalence of HCV infection between cases and controls (3.3% vs. 2.7%, p = 0.019). The covariate-adjusted odds ratio (OR) of HBV infection in patients with HNC relative to controls was 1.219 (95% CI = 1.093~1.359). Additionally, the adjusted OR of HCV infection in patients with HNC was 1.221 (95% CI = 1.023~1.457) compared to controls. Furthermore, patients with oropharyngeal cancer were more likely to have HCV infection than controls (adjusted OR = 2.142, 95% CI = 1.171~3.918). Our study provides evidence that suggests a potential association between HBV and HCV infections and the risk of HNC.
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Affiliation(s)
- Shih-Han Hung
- Department of Otolaryngology, School of Medicine, Taipei Medical University, Taipei 110, Taiwan;
- Department of Otolaryngology, Wan Fang Hospital, Taipei 110, Taiwan
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Tzong-Hann Yang
- Department of Otorhinolaryngology, Taipei City Hospital, Taipei 110, Taiwan;
- Department of Speech, Language and Audiology, National Taipei University of Nursing and Health, Taipei 112, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Center of General Education, University of Taipei, Taipei 112, Taiwan
- Research Center of Sleep Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;
| | - Yen-Fu Cheng
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan;
- Research Center of Sleep Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Chin-Shyan Chen
- Research Center of Sleep Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;
- Department of Economics, National Taipei University, New Taipei City 112, Taiwan
| | - Herng-Ching Lin
- School of Health Care Administration, College of Management, Taipei Medical University, Taipei 110, Taiwan
- Research Center of Sleep Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
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16
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Ahmed K, Jha S. Oncoviruses: How do they hijack their host and current treatment regimes. Biochim Biophys Acta Rev Cancer 2023; 1878:188960. [PMID: 37507056 DOI: 10.1016/j.bbcan.2023.188960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/05/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Abstract
Viruses have the ability to modulate the cellular machinery of their host to ensure their survival. While humans encounter numerous viruses daily, only a select few can lead to disease progression. Some of these viruses can amplify cancer-related traits, particularly when coupled with factors like immunosuppression and co-carcinogens. The global burden of cancer development resulting from viral infections is approximately 12%, and it arises as an unfortunate consequence of persistent infections that cause chronic inflammation, genomic instability from viral genome integration, and dysregulation of tumor suppressor genes and host oncogenes involved in normal cell growth. This review provides an in-depth discussion of oncoviruses and their strategies for hijacking the host's cellular machinery to induce cancer. It delves into how viral oncogenes drive tumorigenesis by targeting key cell signaling pathways. Additionally, the review discusses current therapeutic approaches that have been approved or are undergoing clinical trials to combat malignancies induced by oncoviruses. Understanding the intricate interactions between viruses and host cells can lead to the development of more effective treatments for virus-induced cancers.
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Affiliation(s)
- Kainat Ahmed
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
| | - Sudhakar Jha
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA.
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17
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Tsutsumi Y, Ito S, Shiratori S, Teshima T. Hepatitis C Virus (HCV)-Ribonucleic Acid (RNA) As a Biomarker for Lymphoid Malignancy with HCV Infection. Cancers (Basel) 2023; 15:2852. [PMID: 37345190 DOI: 10.3390/cancers15102852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/15/2023] [Accepted: 05/15/2023] [Indexed: 06/23/2023] Open
Abstract
The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in the treatment of lymphoma, during which the immortalization and proliferation of lymphocytes occur, which leads to the possibility of further stimulating cytokines and the like and possibly to the development of lymphoid malignancy. There are also cases in which the disappearance of lymphoid malignancy has been observed by treating HCV and suppressing HCV-Ribonucleic acid (RNA), as well as cases of recurrence with an increase in HCV-RNA. While HCV-associated lymphoma has a poor prognosis, improving the prognosis with Direct Acting Antivirals (DAA) has recently been reported. The reduction and eradication of HCV-RNA by means of DAA is thus important for the treatment of lymphoid malignancy associated with HCV infection, and HCV-RNA can presumably play a role as a biomarker. This review provides an overview of what is currently known about HCV-associated lymphoma, its epidemiology, the mechanisms underlying the progression to lymphoma, its treatment, the potential and limits of HCV-RNA as a therapeutic biomarker, and biomarkers that are expected now that DAA therapy has been developed.
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Affiliation(s)
- Yutaka Tsutsumi
- Department of Hematology, Hakodate Municipal Hospital, Hakodate, 1-10-1, Minato-cho, Hakodate 041-8680, Japan
| | - Shinichi Ito
- Department of Hematology, Hakodate Municipal Hospital, Hakodate, 1-10-1, Minato-cho, Hakodate 041-8680, Japan
| | - Souichi Shiratori
- Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
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18
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Neoplastic and Autoimmune Comorbidities in Patients with Primary Cutaneous B-Cell Lymphoma. Hematol Rep 2023; 15:157-165. [PMID: 36975729 PMCID: PMC10048514 DOI: 10.3390/hematolrep15010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/11/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
Primary cutaneous B-cell lymphomas (PCBCLs) constitute a rare subset of non-Hodgkin lymphoma (NHL), with distinctive clinical and biological characteristics. The risk of autoimmune or neoplastic comorbidities in subjects with NHL has been extensively reported in the literature, but the data available are not directly applicable to PCBCLs. The aim of our study was to determine the frequency of relevant medical conditions, with a primary focus on autoimmune and neoplastic disorders, in subjects with PCBCL. We performed a retrospective observational study involving 56 patients diagnosed histologically with PCBCL and 54 sex- and age-matched controls. Our results show a statistically significant association for neoplastic comorbidities in general (41.1% vs. 22.2%, p = 0.034) and hematological malignancies specifically (19.6% vs. 1.9%, p = 0.0041) with PCBCL compared to controls. We did not highlight a statistically significant difference in the frequency of autoimmune comorbidities (21.4% vs. 9.3%, p = 0.1128) and of chronic viral hepatitis (7.1% vs. 0, p = 0.1184). Finally, type 2 diabetes (19.6% vs. 1.9%, p = 0.0041) was significantly associated with PCBCL. Our preliminary data supporting the association between PCBCLs and neoplastic disorders suggest that altered immune surveillance may be a common predisposing mechanism.
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19
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Antropova E, Khlebodarova T, Demenkov P, Venzel A, Ivanisenko N, Gavrilenko A, Ivanisenko T, Adamovskaya A, Revva P, Lavrik I, Ivanisenko V. Computer analysis of regulation of hepatocarcinoma marker genes hypermethylated by HCV proteins. Vavilovskii Zhurnal Genet Selektsii 2022; 26:733-742. [PMID: 36714033 PMCID: PMC9840909 DOI: 10.18699/vjgb-22-89] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 01/07/2023] Open
Abstract
Hepatitis C virus (HCV) is a risk factor that leads to hepatocellular carcinoma (HCC) development. Epigenetic changes are known to play an important role in the molecular genetic mechanisms of virus-induced oncogenesis. Aberrant DNA methylation is a mediator of epigenetic changes that are closely associated with the HCC pathogenesis and considered a biomarker for its early diagnosis. The ANDSystem software package was used to reconstruct and evaluate the statistical significance of the pathways HCV could potentially use to regulate 32 hypermethylated genes in HCC, including both oncosuppressor and protumorigenic ones identified by genome-wide analysis of DNA methylation. The reconstructed pathways included those affecting protein-protein interactions (PPI), gene expression, protein activity, stability, and transport regulations, the expression regulation pathways being statistically significant. It has been shown that 8 out of 10 HCV proteins were involved in these pathways, the HCV NS3 protein being implicated in the largest number of regulatory pathways. NS3 was associated with the regulation of 5 tumor-suppressor genes, which may be the evidence of its central role in HCC pathogenesis. Analysis of the reconstructed pathways has demonstrated that following the transcription factor inhibition caused by binding to viral proteins, the expression of a number of oncosuppressors (WT1, MGMT, SOCS1, P53) was suppressed, while the expression of others (RASF1, RUNX3, WIF1, DAPK1) was activated. Thus, the performed gene-network reconstruction has shown that HCV proteins can influence not only the methylation status of oncosuppressor genes, but also their transcriptional regulation. The results obtained can be used in the search for pharmacological targets to develop new drugs against HCV-induced HCC.
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Affiliation(s)
- E.A. Antropova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Scences, Novosibirsk, Russia
| | - T.M. Khlebodarova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Scences, Novosibirsk, RussiaKurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia
| | - P.S. Demenkov
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Scences, Novosibirsk, RussiaKurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia
| | - A.S. Venzel
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Scences, Novosibirsk, RussiaKurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia
| | - N.V. Ivanisenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Scences, Novosibirsk, RussiaKurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia
| | - A.D. Gavrilenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Scences, Novosibirsk, RussiaNovosibirsk State University, Novosibirsk, Russia
| | - T.V. Ivanisenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Scences, Novosibirsk, RussiaKurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia
| | - A.V. Adamovskaya
- Kurchatov Genomic Center of ICG SB RAS, Novosibirsk, RussiaNovosibirsk State University, Novosibirsk, Russia
| | - P.M. Revva
- Kurchatov Genomic Center of ICG SB RAS, Novosibirsk, RussiaKurchatov Genomic Center of ICG SB RAS, Novosibirsk, Russia
| | - I.N. Lavrik
- Translational Inflammation Research, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - V.A. Ivanisenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Scences, Novosibirsk, RussiaKurchatov Genomic Center of ICG SB RAS, Novosibirsk, RussiaNovosibirsk State University, Novosibirsk, Russia
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20
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Second malignant neoplasms in lymphomas, secondary lymphomas and lymphomas in metabolic disorders/diseases. Cell Biosci 2022; 12:30. [PMID: 35279210 PMCID: PMC8917635 DOI: 10.1186/s13578-022-00763-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 02/14/2022] [Indexed: 12/02/2022] Open
Abstract
With inconsistent findings, evidence has been obtained in recent years that metabolic disorders are closely associated with the development of lymphomas. Studies and multiple analyses have been published also indicating that some solid tumor survivors develop a secondary lymphoma, whereas some lymphoma survivors subsequently develop a second malignant neoplasm (SMN), particularly solid tumors. An interaction between the multiple etiologic factors such as genetic factors and late effects of cancer therapy may play an important role contributing to the carcinogenesis in patients with metabolic diseases or with a primary cancer. In this review, we summarize the current knowledge of the multiple etiologic factors for lymphomagenesis, focusing on the SMN in lymphoma, secondary lymphomas in primary cancers, and the lymphomas associated to metabolic disorders/diseases, which have been received less attention previously. Further, we also review the data of coexistence of lymphomas and hepatocellular carcinoma (HCC) in patients with infection of hepatitis C virus and hepatitis B virus.
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21
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Mazzaro C, Bomben R, Gragnani L, Visentini M, Pozzato G, Pozzo F, Zucchetto A, Gattei V. Hepatitis C virus-associated B-cell lymphomas: The importance of the new direct antiviral agent therapy. Semin Hematol 2022; 59:177-182. [PMID: 36805885 DOI: 10.1053/j.seminhematol.2022.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/23/2022] [Accepted: 11/27/2022] [Indexed: 11/30/2022]
Abstract
Hepatitis C virus (HCV) is a hepatotropic and lymphotropic virus, responsible for both chronic hepatitis and extra-hepatic manifestations. Multiple epidemiologic, clinical, biological, and molecular studies have suggested that HCV plays a causal role also in the development of several lymphoproliferative disorders, either benign, such as mixed cryoglobulinemia, or malignant, such as B-cell non-Hodgkin lymphomas (NHL). Chronic viral antigenic stimulation of B-lymphocytes plays a fundamental basic role from the onset of lymphoma to its final steps. In the past, several studies demonstrated that the association of pegylated interferon plus ribavirin was able to eradicate HCV, with subsequent regression of indolent B-cell low-grade NHL. Other studies have demonstrated that direct antiviral agents (DAAs) therapy have some efficacy in HCV-associated NHL, particularly in patients with low-grade NHL or marginal zone-lymphoma, but these results need to be confirmed in larger studies with longer follow-up. The response rate of antiviral therapy seems favorable also in high grade NHL when DAAs therapy is administered in combination with chemotherapy and therefore antiviral therapy should be considered as a first-line approach in HCV-related NHL.
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Affiliation(s)
- Cesare Mazzaro
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy.
| | - Riccardo Bomben
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy
| | - Laura Gragnani
- MASVE Interdepartmental Center, Department of Experimental and Clinical Medicine, University of Florence, Center for Research and Innovation CRIA-MASVE, Firenze, Italy
| | - Marcella Visentini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Gabriele Pozzato
- Clinical and Surgical Sciences, University of Trieste, Trieste, Italy
| | - Federico Pozzo
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy
| | - Antonella Zucchetto
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy
| | - Valter Gattei
- Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy
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22
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Bilajac E, Mahmutović L, Lundstrom K, Glamočlija U, Šutković J, Sezer A, Hromić-Jahjefendić A. Viral Agents as Potential Drivers of Diffuse Large B-Cell Lymphoma Tumorigenesis. Viruses 2022; 14:2105. [PMID: 36298660 PMCID: PMC9610751 DOI: 10.3390/v14102105] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/19/2022] [Indexed: 04/22/2025] Open
Abstract
Among numerous causative agents recognized as oncogenic drivers, 13% of total cancer cases occur as a result of viral infections. The intricacy and diversity of carcinogenic processes, however, raise significant concerns about the mechanistic function of viruses in cancer. All tumor-associated viruses have been shown to encode viral oncogenes with a potential for cell transformation and the development of malignancies, including diffuse large B-cell lymphoma (DLBCL). Given the difficulties in identifying single mechanistic explanations, it is necessary to combine ideas from systems biology and viral evolution to comprehend the processes driving viral cancer. The potential for more efficient and acceptable therapies lies in targeted medicines that aim at viral proteins or trigger immune responses to either avoid infection or eliminate infected or cancerous cells. In this review, we aim to describe the role of viral infections and their mechanistic approaches in DLBCL tumorigenesis. To the best of our knowledge, this is the first review summarizing the oncogenic potential of numerous viral agents in DLBCL development.
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Affiliation(s)
- Esma Bilajac
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnička cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
| | - Lejla Mahmutović
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnička cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
| | | | - Una Glamočlija
- Department of Pharmaceutical Biochemistry and Laboratory Diagnostics, University of Sarajevo, Faculty of Pharmacy, Zmaja od Bosne 8, 71 000 Sarajevo, Bosnia and Herzegovina
- School of Medicine, University of Mostar, Zrinskog Frankopana 34, 88 000 Mostar, Bosnia and Herzegovina
- Scientific-Research Unit, Bosnalijek JSC, Jukićeva 53, 71 000 Sarajevo, Bosnia and Herzegovina
| | - Jasmin Šutković
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnička cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
| | - Abas Sezer
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnička cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
| | - Altijana Hromić-Jahjefendić
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnička cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
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23
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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24
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Viral Encoded miRNAs in Tumorigenesis: Theranostic Opportunities in Precision Oncology. Microorganisms 2022; 10:microorganisms10071448. [PMID: 35889167 PMCID: PMC9321719 DOI: 10.3390/microorganisms10071448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022] Open
Abstract
About 15% of all human cancers have a viral etiology. Although progress has been made, understanding the viral oncogenesis and associated molecular mechanisms remain complex. The discovery of cellular miRNAs has led to major breakthroughs. Interestingly, viruses have also been discovered to encode their own miRNAs. These viral, small, non-coding miRNAs are also known as viral-miRNAs (v-miRNAs). Although the function of v-miRNAs largely remains to be elucidated, their role in tumorigenesis cannot be ignored. V-miRNAs have also been shown to exploit the cellular machinery to benefit viral replication and survival. Although the discovery of Hepatitis C virus (HCV), and its viral miRNAs, is a work in progress, the existence of HPV-, EBV-, HBV-, MCPyV- and KSHV-encoded miRNA has been documented. V-miRNAs have been shown to target host factors to advance tumorigenesis, evade and suppress the immune system, and deregulate both the cell cycle and the apoptotic machinery. Although the exact mechanisms of v-miRNAs-induced tumorigenesis are still unclear, v-miRNAs are active role-players in tumorigenesis, viral latency and cell transformation. Furthermore, v-miRNAs can function as posttranscriptional gene regulators of both viral and host genes. Thus, it has been proposed that v-miRNAs may serve as diagnostic biomarkers and therapeutic targets for cancers with a viral etiology. Although significant challenges exist in their clinical application, emerging reports demonstrate their potent role in precision medicine. This review will focus on the roles of HPV-, HCV-, EBV-, HBV-, MCPyV-, and KSHV-produced v-miRNAs in tumorigenesis, as effectors in immune evasion, as diagnostic biomarkers and as novel anti-cancer therapeutic targets. Finally, it will discuss the challenges and opportunities associated with v-miRNAs theranostics in precision oncology.
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Tella SH, Kommalapati A, Mahipal A, Jin Z. First-Line Targeted Therapy for Hepatocellular Carcinoma: Role of Atezolizumab/Bevacizumab Combination. Biomedicines 2022; 10:1304. [PMID: 35740326 PMCID: PMC9220769 DOI: 10.3390/biomedicines10061304] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/14/2022] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive malignancy accounting for 90% of primary liver malignancies. Therapeutic options for HCC are primarily based on the baseline functional status, the extent of disease at presentation and the underlying liver function that is clinically evaluated by the Barcelona-Clinic Liver Cancer system and Child−Pugh score. In patients with advanced HCC, the United States Food and Drug Administration (US-FDA) approved systemic therapies include the combination of atezolizumab−bevacizumab, sorafenib, and lenvatinib in the first line setting while cabozantinib, regorafenib, ramucirumab (in patients with alfa-fetoprotein [AFP] > 400 ng/mL), pembrolizumab, nivolumab, and nivolumab-ipilimumab combination are reserved for patients who progressed on sorafenib. European Medical Agency (EMA) approved the use of atezolizumab−bevacizumab, sorafenib, and lenvatinib in the first line setting, while cabozantinib, regorafenib, and ramucirumab (in patients with alfa-fetoprotein [AFP] > 400 ng/mL) are approved for use in patients that progressed on first-line therapy. In the first line setting, sorafenib demonstrated a median overall survival (OS) benefit of 3 months as compared to that of best supportive care in randomized phase III trials, while lenvatinib was shown to be non-inferior to sorafenib. Recently, phase 3 studies with immunotherapeutic agents including atezolizumab plus a bevacizumab combination and tremelimumab plus durvalumab combination demonstrated a better OS and progression free survival (PFS) compared to sorafenib in the first-line setting, making them attractive first-line options in advanced HCC. In this review, we outlined the tumorigenesis and immune landscape of HCC in brief and discussed the role and rationale of combining immunotherapy and anti-VEGF therapy. We further expanded on potential limitations and the future directions of immunotherapy in combination with targeted agents in the management of advanced HCC.
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Affiliation(s)
| | | | | | - Zhaohui Jin
- Department of Medical Oncology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA; (S.H.T.); (A.K.); (A.M.)
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Shilova ON, Tsyba DL, Shilov ES. Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis. Mol Biol 2022; 56:46-58. [PMID: 35194245 PMCID: PMC8852905 DOI: 10.1134/s002689332201006x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/23/2021] [Accepted: 06/01/2021] [Indexed: 01/02/2023]
Abstract
Proteins of the AID/APOBEC family are capable of cytidine deamination in nucleic acids forming uracil. These enzymes are involved in mRNA editing, protection against viruses, the introduction of point mutations into DNA during somatic hypermutation, and antibody isotype switching. Since these deaminases, especially AID, are potent mutagens, their expression, activity, and specificity are regulated by several intracellular mechanisms. In this review, we discuss the mechanisms of impaired expression and activation of AID/APOBEC proteins in human tumors and their role in carcinogenesis and tumor progression. Also, the diagnostic and potential therapeutic value of increased expression of AID/APOBEC in different types of tumors is analyzed. We assume that in the case of solid tumors, increased expression of endogenous deaminases can serve as a marker of response to immunotherapy since multiple point mutations in host DNA could lead to amino acid substitutions in tumor proteins and thereby increase the frequency of neoepitopes.
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Affiliation(s)
- O. N. Shilova
- Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
| | - D. L. Tsyba
- Pavlov First State Medical University, 197022 St. Petersburg, Russia
- Sirius University of Science and Technology, 354340 Sochi, Russia
| | - E. S. Shilov
- Faculty of Biology, Moscow State University, 119234 Moscow, Russia
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Badami E, Carcione C, Chinnici CM, Tinnirello R, Conaldi PG, Iannolo G. HCV Interplay With Mir34a: Implications in Hepatocellular Carcinoma. Front Oncol 2022; 11:803278. [PMID: 35127513 PMCID: PMC8812294 DOI: 10.3389/fonc.2021.803278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/27/2021] [Indexed: 12/24/2022] Open
Abstract
Since its identification, HCV has been considered one of the main causes of hepatitis and liver cancer. Currently, the molecular mechanisms of HCC development induced by HCV infection have not been sufficiently clarified. The recent discovery of novel treatments that inhibit HCV replication gave rise to new questions concerning HCC mechanisms. In particular, the HCV eradication mediated by new direct-acting antiviral (DAAs) drugs does not exclude the possibility of de novo HCC development; this finding opened more questions on the interplay between liver cells and the virus. Different groups have investigated the pathways leading to cancer recurrence in patients treated with DAAs. For this reason, we tried to gain molecular insights into the changes induced by HCV infection in the target liver cells. In particular, we observed an increase in microRNA34a (miR34a) expression following HCV infection of HCC cell line Huh7.5. In addition, Huh7.5 treated with extracellular vesicles (EVs) from the previously HCV-infected Huh7.5 underwent apoptosis. Since miR34 expression was increased in Huh7.5 EVs, we hypothesized a paracrine mechanism of viral infection mediated by miR34a cargo of EVs. The balance between viral infection and cell transformation may raise some questions on the possible use of antiviral drugs in association with antineoplastic treatment.
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Affiliation(s)
- Ester Badami
- Department of Research, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS ISMETT), Palermo, Italy
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo, Italy
| | - Claudia Carcione
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo, Italy
| | - Cinzia Maria Chinnici
- Department of Research, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS ISMETT), Palermo, Italy
- Regenerative Medicine and Immunotherapy Area, Fondazione Ri.MED, Palermo, Italy
| | - Rosaria Tinnirello
- Neuroscience Unit, Consiglio Nazionale delle Ricerche (CNR), Institute of Biomedicine and Molecular Immunology, Palermo, Italy
| | - Pier Giulio Conaldi
- Department of Research, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS ISMETT), Palermo, Italy
| | - Gioacchin Iannolo
- Department of Research, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS ISMETT), Palermo, Italy
- *Correspondence: Gioacchin Iannolo, ; ; orcid.org/0000-0002-7710-4735
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Cacoub P, Comarmond C, Vieira M, Régnier P, Saadoun D. HCV-related lymphoproliferative disorders in the direct-acting antiviral era: From mixed cryoglobulinaemia to B-cell lymphoma. J Hepatol 2022; 76:174-185. [PMID: 34600000 DOI: 10.1016/j.jhep.2021.09.023] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/31/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023]
Abstract
HCV has been shown to induce many B-cell lymphoproliferative disorders. B lymphocytes specialise in producing immunoglobulins and, during chronic HCV infection, they can cause manifestations ranging from polyclonal hypergammaglobulinaemia without clinical repercussions, through mixed cryoglobulinaemic vasculitis to B-cell non-Hodgkin lymphoma. This spectrum is supported by substantial epidemiological, pathophysiological and therapeutic data. Many, although not all, of the pathogenic pathways leading from one extreme to another have been decrypted. Chronic viral antigen stimulation of B lymphocytes has a central role until the final steps before overt malignancy. This has direct implications for treatment strategies, which always include the use of direct-acting antivirals sometimes alongside immunosuppressants. The role of direct-acting antivirals has been well established in patients with cryoglobulinaemia vasculitis. However, their positive impact on B-cell non-Hodgkin lymphoma needs to be confirmed in larger studies with longer follow-up.
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Affiliation(s)
- Patrice Cacoub
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France.
| | - Cloé Comarmond
- AP-HP, Lariboisière Hospital, Department of Internal Medicine and Clinical Immunology, Paris, France
| | - Matheus Vieira
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France
| | - Paul Régnier
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France
| | - David Saadoun
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France; Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose inflammatoire, F-75013, Paris, France; Institut National de la Santé et de la Recherche Médicale, INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005, Paris, France
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Occult Infection with Hepatitis C Virus: Looking for Clear-Cut Boundaries and Methodological Consensus. J Clin Med 2021; 10:jcm10245874. [PMID: 34945170 PMCID: PMC8707082 DOI: 10.3390/jcm10245874] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/11/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023] Open
Abstract
The sustained virologic response and elimination of HCV is widely viewed as a true cure of chronic hepatitis C as it associates with amelioration of histological liver damage and improved clinical outcomes. Therefore, the existence and clinical burden of occult HCV infection (OCI) has been a controversial issue for many years. In this review, we summarize recently published data that adds new information on the molecular and clinical background of OCI and its epidemiological significance. We also identify and discuss the most important methodological pitfalls, which can be a source of inconsistency between studies. Data that have accumulated so far, strongly support the existence of extrahepatic HCV replication in individuals negative for serum HCV-RNA by conventional clinical tests. OCI emerges as a condition where the immune system is unable to fully resolve infection but it is continuously stimulated by low levels of HCV antigens, leading to progression of liver pathology and extrahepatic HCV-related complications. Moreover, the development of monitoring strategies or management guidelines for OCI is still hampered by the lack of clear definition and the confusion regarding its clinical significance. Careful study design and the introduction of uniform protocols for the detection of low-level HCV-RNA are crucial for obtaining reliable data on OCI.
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Tsai YF, Liu YC, Yang CI, Chuang TM, Ke YL, Yeh TJ, Gau YC, Du JS, Wang HC, Cho SF, Hsu CM, Wu PF, Huang CI, Huang CF, Yu ML, Dai CY, Hsiao HH. Poor Prognosis of Diffuse Large B-Cell Lymphoma with Hepatitis C Infection. J Pers Med 2021; 11:844. [PMID: 34575621 PMCID: PMC8465128 DOI: 10.3390/jpm11090844] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) in diffuse large B-cell lymphoma (DLBCL) is associated with a higher prevalence and distinctive clinical characteristics and outcomes. METHODS A retrospective analysis of adult DLBCL patients from 2011 to 2015 was studied. RESULTS A total of 206 adult DLBCL were enrolled with 22 (10.7%) HCV-positive patients. Compared to HCV-negative patients, the HCV-positive group had a poor performance status (p = 0.011), lower platelet count (p = 0.029), and higher spleen and liver involvement incidences (liver involvement, p = 0.027, spleen involvement, p = 0.026), and they received fewer cycles of chemotherapy significantly due to morbidity and mortality (p = 0.048). Overall survival was shorter in HCV-positive DLBCL (25.3 months in HCV-positive vs. not reached (NR), p = 0.049). With multivariate analysis, poor performance status (p < 0.001), advanced stage (p < 0.001), less chemotherapy cycles (p < 0.001), and the presence of liver toxicity (p = 0.001) contributed to poor OS in DLBCL. Among HCV-positive DLBCL, the severity of liver fibrosis was the main risk factor related to death. CONCLUSION Inferior survival of HCV-positive DLBCL was observed and associated with poor performance status, higher numbers of complications, and intolerance of treatment, leading to fewer therapy. Therefore, anti-HCV therapy, such as direct-acting antiviral agents, might benefit these patients in the future.
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Affiliation(s)
- Yu-Fen Tsai
- Department of Hematology & Oncology, E-Da Cancer Hospital, Kaohsiung 824, Taiwan;
- School of Chinese Medicine for Post Baccalaureate, College of Medicine, I-Shou University, Kaohsiung 824, Taiwan
| | - Yi-Chang Liu
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-I.H.); (C.-F.H.); (M.-L.Y.); (C.-Y.D.)
| | - Ching-I Yang
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
- Specialist Nurse and Surgical Nurse Practitioner Office, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Tzer-Ming Chuang
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
| | - Ya-Lun Ke
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
| | - Tsung-Jang Yeh
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
| | - Yuh-Ching Gau
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
| | - Jeng-Shiun Du
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
| | - Hui-Ching Wang
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-I.H.); (C.-F.H.); (M.-L.Y.); (C.-Y.D.)
| | - Shih-Feng Cho
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-I.H.); (C.-F.H.); (M.-L.Y.); (C.-Y.D.)
| | - Chin-Mu Hsu
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
| | - Pey-Fang Wu
- Division of Hepatobiliary Ward, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Ching-I Huang
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-I.H.); (C.-F.H.); (M.-L.Y.); (C.-Y.D.)
- Division of Hepatobiliary Ward, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Chung-Feng Huang
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-I.H.); (C.-F.H.); (M.-L.Y.); (C.-Y.D.)
- Division of Hepatobiliary Ward, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Ming-Lung Yu
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-I.H.); (C.-F.H.); (M.-L.Y.); (C.-Y.D.)
- Division of Hepatobiliary Ward, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Chia-Yen Dai
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-I.H.); (C.-F.H.); (M.-L.Y.); (C.-Y.D.)
- Division of Hepatobiliary Ward, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Hui-Hua Hsiao
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (Y.-C.L.); (C.-I.Y.); (T.-M.C.); (Y.-L.K.); (T.-J.Y.); (Y.-C.G.); (J.-S.D.); (H.-C.W.); (S.-F.C.); (C.-M.H.)
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-I.H.); (C.-F.H.); (M.-L.Y.); (C.-Y.D.)
- Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Meshcheryakova A, Pietschmann P, Zimmermann P, Rogozin IB, Mechtcheriakova D. AID and APOBECs as Multifaceted Intrinsic Virus-Restricting Factors: Emerging Concepts in the Light of COVID-19. Front Immunol 2021; 12:690416. [PMID: 34276680 PMCID: PMC8282206 DOI: 10.3389/fimmu.2021.690416] [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: 04/02/2021] [Accepted: 06/07/2021] [Indexed: 12/23/2022] Open
Abstract
The AID (activation-induced cytidine deaminase)/APOBEC (apolipoprotein B mRNA editing enzyme catalytic subunit) family with its multifaceted mode of action emerges as potent intrinsic host antiviral system that acts against a variety of DNA and RNA viruses including coronaviruses. All family members are cytosine-to-uracil deaminases that either have a profound role in driving a strong and specific humoral immune response (AID) or restricting the virus itself by a plethora of mechanisms (APOBECs). In this article, we highlight some of the key aspects apparently linking the AID/APOBECs and SARS-CoV-2. Among those is our discovery that APOBEC4 shows high expression in cell types and anatomical parts targeted by SARS-CoV-2. Additional focus is given by us to the lymphoid structures and AID as the master regulator of germinal center reactions, which result in antibody production by plasma and memory B cells. We propose the dissection of the AID/APOBECs gene signature towards decisive determinants of the patient-specific and/or the patient group-specific antiviral response. Finally, the patient-specific mapping of the AID/APOBEC polymorphisms should be considered in the light of COVID-19.
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Affiliation(s)
- Anastasia Meshcheryakova
- Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Peter Pietschmann
- Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | | | - Igor B Rogozin
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, United States
| | - Diana Mechtcheriakova
- Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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Ciancio A. Impact of Direct Antiviral Agents (DAAs) on B-cell Non Hodgkin's Lymphoma in patients with chronic hepatitis C. Minerva Gastroenterol (Torino) 2021; 67:227-233. [PMID: 33856146 DOI: 10.23736/s2724-5985.21.02834-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The relationship between HCV infection and extrahepatic manifestations has been demonstrated by epidemiological, clinical, immunological and pathological studies. Patients with HCV infection have an increased risk of morbidity and mortality related to these non-liver diseases. For these reasons, HCV chronic infection should be considered a systemic disease in which extrahepatic manifestations increase the severity of the disease. HCV-extrahepatic manifestations may severely affect the overall prognosis, while viral eradication significantly reduces non-liver related deaths. Over the past 5 years, treatment of chronic HCV infection in patients with hematologic malignancies has evolved rapidly and effective and safe direct-acting antivirals (DAAs) have become the standardof-care treatment. The choice of regimens with DAAs should be individualized after thorough assessment for potential hematologic toxic effects and drug-drug interactions. Elimination of HCV from infected cancer patients confers virologic, hepatic, and oncologic benefits.
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Affiliation(s)
- Alessia Ciancio
- Dipartimento di Scienze Mediche, Scuola di Medicina, Università degli Studi di Torino, Turin, Italy -
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Leone V, Ali A, Weber A, Tschaharganeh DF, Heikenwalder M. Liver Inflammation and Hepatobiliary Cancers. Trends Cancer 2021; 7:606-623. [PMID: 33674229 DOI: 10.1016/j.trecan.2021.01.012] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 12/17/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
Immune regulation has an important role in cancer development, particularly in organs with continuous exposure to environmental pathogens, such as the liver and gastrointestinal tract. Chronic liver inflammation can lead to the development of hepatobiliary cancers, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or combined HCC (cHCC)-CCA. In this review, we discuss the link between oxidative stress and the hepatic immune compartments, as well as how these factors trigger hepatocyte damage, proliferation, and eventually cancer initiation and its sustainment. We further give an overview of new anticancer therapies based on immunomodulation.
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Affiliation(s)
- Valentina Leone
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Research Unit Radiation Cytogenetics, Helmholtz Zentrum München Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany
| | - Adnan Ali
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Achim Weber
- Department of Pathology and Molecular Pathology, Institute of Molecular Cancer Research (IMCR), University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland
| | - Darjus Felix Tschaharganeh
- Helmholtz-University Group Cell Plasticity and Epigenetic Remodeling, German Cancer Research Center (DKFZ) and Institute of Pathology University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
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Alcohol Intake and Mortality in Patients With Chronic Viral Hepatitis: A Nationwide Cohort Study. Am J Gastroenterol 2021; 116:329-335. [PMID: 33038136 DOI: 10.14309/ajg.0000000000000966] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 08/26/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION We evaluated the association between alcohol intake and all-cause and cause-specific mortality in subjects with chronic viral hepatitis, using nationwide population-based cohort study. METHODS A total of 364,361 men and women aged 40-84 years who underwent health screening examination between January 2002 and December 2013 that included assessment of frequency and amount of alcohol consumption were assessed for all-cause and cause-specific mortality. RESULTS In participants without chronic viral hepatitis, the fully adjusted hazard ratios (HRs) for all-cause mortality comparing light, moderate, and heavy drinkers with nondrinkers were 0.92 (95% confidence interval [CI] 0.87-0.98), 1.08 (95% CI 1.01-1.16), and 1.51 (95% CI 1.33-1.72), respectively. In participants with chronic viral hepatitis, the corresponding HRs were 1.19 (95% CI 1.05-1.36), 1.23 (95% CI 1.06-1.43), and 1.69 (95% CI 1.28-2.24), respectively (P value for alcohol intake by chronic viral hepatitis interaction <0.001). Compared with participants without chronic viral hepatitis, those with chronic viral hepatitis had substantially elevated liver cancer or liver disease (HR 10.85, 95% CI 9.74-12.09) and extrahepatic cancer mortality (HR 1.37, 95% CI 1.26-1.49). In patients with chronic viral hepatitis, the high mortality due to liver cancer or liver disease and the positive association of alcohol intake with liver cancer or liver disease mortality explained the positive association of alcohol intake with all-cause mortality. DISCUSSION Even light to moderate alcohol intake was associated with increased all-cause mortality in individuals with chronic viral hepatitis. Clinicians and public health campaigns should advise against any amount of alcohol intake in individuals with chronic viral hepatitis.
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Gillman R, Lopes Floro K, Wankell M, Hebbard L. The role of DNA damage and repair in liver cancer. Biochim Biophys Acta Rev Cancer 2020; 1875:188493. [PMID: 33316376 DOI: 10.1016/j.bbcan.2020.188493] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/25/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is rapidly becoming a major cause of global mortality due to the ever-increasing prevalence of obesity. DNA damage is known to play an important role in cancer initiation, however DNA repair systems are also vital for the survival of cancer cells. Given the function of the liver and its exposure to the gut, it is likely that DNA damage and repair would be of particular importance in hepatocellular carcinoma. However, many contemporary reports have neglected the role of individual pathways of DNA damage and repair in their hypotheses. This review, therefore, aims to provide a concise overview for researchers in the field of liver cancer to understand the pathways of DNA damage and repair and their individual roles in hepatocellular carcinoma.
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Affiliation(s)
- Rhys Gillman
- Department of Molecular and Cell Biology, College of Public Health, Medical, and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia
| | - Kylie Lopes Floro
- Department of Molecular and Cell Biology, College of Public Health, Medical, and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia; Department of Radiation Oncology, Townsville University Hospital, Townsville, Queensland, Australia
| | - Miriam Wankell
- Department of Molecular and Cell Biology, College of Public Health, Medical, and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia; Australian Institute for Tropical Health and Medicine, Townsville, Queensland, Australia
| | - Lionel Hebbard
- Department of Molecular and Cell Biology, College of Public Health, Medical, and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia; Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia; Australian Institute for Tropical Health and Medicine, Townsville, Queensland, Australia.
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Pozzato G, Mazzaro C, Gattei V. Hepatitis C virus-associated non-Hodgkin lymphomas: the endless history. Minerva Med 2020; 112:215-227. [PMID: 33263375 DOI: 10.23736/s0026-4806.20.07184-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hepatitis C virus (HCV) is a global population problem due to its high prevalence worldwide. In the prognosis of patients with HCV not only hepatic but increasingly frequent of extrahepatic HCV manifestations, such as mixed cryoglobulinemia (MC) and non-Hodgkin's lymphoma (NHL), are important. The role of the HCV virus in the pathogenesis of lymphoproliferative diseases is confirmed by a large number of epidemiological studies, as well as by the effectiveness of antiviral therapy in patients with non-Hodgkin's lymphoma (NHL). The purpose of the review was to provide an overview of epidemiological and biological data explaining the role of HCV in the development of NHL. The review also discusses HCV-associated NHL treatment by the traditional antiviral therapy (interferon and ribavirin) and by the new direct antiviral agents.
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Affiliation(s)
- Gabriele Pozzato
- Department of Clinical and Surgical Sciences, Maggiore Hospital, University of Trieste, Trieste, Italy -
| | - Cesare Mazzaro
- Unit of Clinical and Experimental Onco-Hematology, CRO Aviano National Cancer Institute IRCCS, Aviano, Pordenone, Italy
| | - Valter Gattei
- Unit of Clinical and Experimental Onco-Hematology, CRO Aviano National Cancer Institute IRCCS, Aviano, Pordenone, Italy
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Chatukuta P, Rey MEC. A cassava protoplast system for screening genes associated with the response to South African cassava mosaic virus. Virol J 2020; 17:184. [PMID: 33228712 PMCID: PMC7685591 DOI: 10.1186/s12985-020-01453-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/09/2020] [Indexed: 01/08/2023] Open
Abstract
Background The study of transient gene expression in cassava plants during virus infection using existing protocols is laborious and may take approximately fifteen weeks due to cassava’s recalcitrance to transformation. The combination of a protoplast system with CRISPR-mediated gene editing promises to shorten the turnaround time from plant tissue culture to high-throughput gene expression screening for candidate genes. Here, we detail a protocol for screening genes associated with the response to South African cassava mosaic virus (SACMV) in cassava protoplasts, with reference to the ubiquitin E3 ligase gene, MeE3L.
Methods Cassava protoplasts of model, and SACMV-susceptible and -tolerant genotypes, were transformed with SACMV infectious clones and/or a CRISPR-editing construct targeting the MeE3L using PEG4000-mediated transfection. DNA and RNA were extracted from transformed protoplasts at 24 h post-transfection. Relative SACMV DNA accumulation was determined via qPCR using DpnI-digested total DNA, MeE3L relative expression was determined via reverse transcriptase qPCR, and results were analysed using one-way ANOVA, Tukey’s HSD test and the 2−ΔΔCTstatistical method. The MeE3L exonic region was sequenced on the ABI 3500XL Genetic Analyzer platform; and sequences were analysed for mutations using MAFTT and MEGA-X software. Construction of a phylogenetic tree was done using the Maximum Likelihood method and Jones-Taylor-Thornton (JTT) matrix-based model. Results The differential expression of unedited and mutant MeE3L during SACMV infection of model, susceptible and tolerant cassava protoplasts was determined within 7 weeks after commencement of tissue culture. The study also revealed that SACMV DNA accumulation in cassava protoplasts is genotype-dependent and induces multiple mutations in the tolerant landrace MeE3L homolog. Notably, the susceptible cassava landrace encodes a RINGless MeE3Lwhich is silenced by SACMV-induced mutations. SACMV also induces mutations which silence the MeE3L RING domain in protoplasts from and tolerant cassava landraces. Conclusions This protocol presented here halves the turnaround time for high-throughput screening of genes associated with the host response to SACMV. It provides evidence that a cassava E3 ligase is associated with the response to SACMV and forms a basis for validation of these findings by in planta functional and interaction studies.
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Affiliation(s)
- Patience Chatukuta
- School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa
| | - Marie Emma Christine Rey
- School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa.
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Ligation-Mediated Polymerase Chain Reaction Detection of 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine and 5-Hydroxycytosine at the Codon 176 of the p53 Gene of Hepatitis C-Associated Hepatocellular Carcinoma Patients. Int J Mol Sci 2020; 21:ijms21186753. [PMID: 32942546 PMCID: PMC7555735 DOI: 10.3390/ijms21186753] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 12/30/2022] Open
Abstract
Molecular mechanisms underlying Hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) pathogenesis are still unclear. Therefore, we analyzed the levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and other oxidative lesions at codon 176 of the p53 gene, as well as the generation of 3-(2-deoxy-β-d-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M1dG), in a cohort of HCV-related HCC patients from Italy. Detection of 8-oxodG and 5-hydroxycytosine (5-OHC) was performed by ligation mediated-polymerase chain reaction assay, whereas the levels of M1dG were measured by chromatography and mass-spectrometry. Results indicated a significant 130% excess of 8-oxodG at –TGC– position of p53 codon 176 in HCV-HCC cases as compared to controls, after correction for age and gender, whereas a not significant increment of 5-OHC at –TGC– position was found. Then, regression models showed an 87% significant excess of M1dG in HCV-HCC cases relative to controls. Our study provides evidence that increased adduct binding does not occur randomly on the sequence of the p53 gene but at specific sequence context in HCV-HCC patients. By-products of lipid peroxidation could also yield a role in HCV-HCC development. Results emphasize the importance of active oxygen species in inducing nucleotide lesions at a p53 mutational hotspot in HCV-HCC patients living in geographical areas without dietary exposure to aflatoxin B1.
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Arai J, Ito T, Shimozuma Y, Uchikoshi M, Nakajima Y, Sakaki M, Uozumi S, Kajiwara A, Sugiura I, Otoyama Y, Nozawa H, Kurihara T, Eguchi J, Nomura N, Sakuma D, Sato M, Deguchi Y, Yoshida H. Decreased expression of interferon-stimulated genes in B cells of patients with chronic hepatitis C during interferon-free therapy potentially suggests the eradication of hepatitis C virus in the B cells: A cohort study. Health Sci Rep 2020; 3:e176. [PMID: 32685701 PMCID: PMC7362757 DOI: 10.1002/hsr2.176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 05/14/2020] [Accepted: 06/03/2020] [Indexed: 01/03/2023] Open
Abstract
AIMS Hepatitis C virus (HCV) infection is monitored by the host innate immunity that includes the endogenous interferon (IFN), which up-regulates IFN-stimulated genes (ISGs). HCV is both hepatotropic and lymphotropic, but HCV replication in lymphoid cells is a controversial issue. Here, we analyzed the mRNA levels of the ISGs in B cells of HCV-infected patients during antiviral therapy and investigated the effects of viral eradication. METHODS One hundred and eighty-one patients with chronic hepatitis C and 26 healthy volunteers were enrolled in this study. Levels of HCV RNA and mRNA of ISGs in B cells isolated from the patients were monitored before, during, and after antiviral therapy. RESULTS HCV RNA was detected in B cells of 133/175 (76.0%) patients who achieved sustained virologic response (SVR) before therapy was started. The positive ratio of HCV RNA in B cells was higher in patients with genotype 1 and the non-major genotype of interleukin 28B. HCV RNA in B cells of most patients disappeared 1 week after antiviral therapy was started. The baseline expression of ISG mRNA was significantly higher in the patients than in the healthy volunteers. Levels of ISG mRNA were increased and remained high throughout the IFN-based therapy. In contrast, levels of ISG mRNA in patients who achieved SVR were significantly decreased 1 week after the IFN-free therapy was started and remained low during the therapy. CONCLUSIONS These results suggested that IFN-free therapy potentially eradicated HCV in the B cells, leading to the down-regulation of endogenous ISGs. The level of ISG mRNA could be used as a marker for viral eradication in B cells.
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Affiliation(s)
- Jun Arai
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Takayoshi Ito
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Yuu Shimozuma
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Manabu Uchikoshi
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Yoko Nakajima
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Masashi Sakaki
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Shojiro Uozumi
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Atsushi Kajiwara
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Ikuya Sugiura
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Yumi Otoyama
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | - Hisako Nozawa
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
| | | | - Junichi Eguchi
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Norihiro Nomura
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Dai Sakuma
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Masashi Sato
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Yoshio Deguchi
- Digestive Disease CenterShowa University Koto Toyosu HospitalTokyoJapan
| | - Hitoshi Yoshida
- Department of Medicine, Division of GastroenterologyShowa University School of MedicineTokyoJapan
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Hong CY, Sinn DH, Kang D, Paik SW, Guallar E, Cho J, Gwak GY. Incidence of extrahepatic cancers among individuals with chronic hepatitis B or C virus infection: A nationwide cohort study. J Viral Hepat 2020; 27:896-903. [PMID: 32340080 DOI: 10.1111/jvh.13304] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 03/25/2020] [Accepted: 04/09/2020] [Indexed: 12/11/2022]
Abstract
This study examined the association between chronic HBV or HCV infection and the risk of extrahepatic cancers. A total of 537 103 adults aged ≥20 years without history of cancer were identified from the Korean National Health Insurance Service-National Sample Cohort between 2003 and 2013. The difference in cancer incidence was compared between those with and without chronic HBV or HCV infection. During 3 854 130 person-years of follow-up (median follow-up: 8.0 years), 19 089 participants developed cancer. After adjusting for sex, body mass index, smoking, drinking, income percentile, residential area and comorbidities, hazard ratios (HRs) for incident extrahepatic cancer were significantly higher in participants with chronic HBV infection (HR: 1.27, 95% confidence interval [CI]: 1.20-1.35), HCV infection (HR: 1.31, 95% CI: 1.16-1.48) or HBV/HCV dual infection (HR: 1.41, 95% CI: 1.31-1.72) compared to participants without HBV or HCV infection. In chronic HBV infection, the cancer risk was higher for haematologic malignancy [HR (95% CI) = 2.46 (1.92-3.15)], gallbladder [1.55 (1.05-2.29)], pancreas [1.52 (1.07-2.15)], stomach [1.39 (1.22-1.58)], lung [1.27 (1.04-1.55)], colorectum [1.21 (1.03-1.42)] and thyroid cancer [1.20 (1.05-1.36)]. In chronic HCV infection, the cancer risk was higher for testis [10.34 (1.35-79.78)], gallbladder [2.90 (1.62-5.18)], prostate [2.51 (1.65-3.82)] and thyroid cancer [1.46 (1.10-1.93)]. In conclusion, chronic HBV or HCV infection was not only associated with an increased risk of liver cancer, but also associated with an increased risk of multiple extrahepatic cancers.
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Affiliation(s)
- Chai Yeong Hong
- Quality Management Division, Intro Biopharma Korea, Gyeonggi-do, South Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Danbee Kang
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Eliseo Guallar
- Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea.,Departments of Epidemiology and Medicine and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institution, Baltimore, MD, USA
| | - Juhee Cho
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea.,Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea.,Departments of Epidemiology and Medicine and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institution, Baltimore, MD, USA
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Sakai H, Miwa T, Ikoma Y, Hanai T, Nakamura N, Imai K, Kitagawa J, Shirakami Y, Kanemura N, Suetsugu A, Takai K, Shiraki M, Shimizu M. Development of diffuse large B-cell lymphoma after sofosbuvir-ledipasvir treatment for chronic hepatitis C: A case report and literature review. Mol Clin Oncol 2020; 13:1. [PMID: 32754315 PMCID: PMC7391802 DOI: 10.3892/mco.2020.2071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022] Open
Abstract
Recently, treatments for chronic hepatitis C virus (HCV) infection have significantly improved by the development of direct-acting antiviral agents (DAAs) and almost all patients with HCV can complete antiviral treatment without apparent adverse events. Malignant lymphoma, particularly B-cell non-Hodgkin's lymphoma, is one of the extrahepatic manifestations associated with chronic HCV infection. The effectiveness of anti-HCV therapy with DAAs for B-cell non-Hodgkin's lymphoma has been demonstrated in recent reports, whereas late-onset B-cell non-Hodgkin's lymphoma after HCV eradication with DAAs has occasionally been reported. In the present study, a 77-year-old man with chronic hepatitis C and intermediate liver cancer risk received sofosbuvir-ledipasvir treatment for 12 weeks. Two months following the end of antiviral therapy, he had achieved sustained virologic response for 8 weeks. However, the patient occasionally found swelling of the right cervical lymph nodes without any subjective symptoms. Lymph node biopsy revealed diffuse large B-cell lymphoma and whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography showed increased FDG uptake in the right cervical, right submandibular, mediastinal and mesenteric lymph nodes. The patient received six courses of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy and achieved complete response at 8 months after chemotherapy initiation. Thus, the development of lymphoid malignancies may arise, even after HCV eradication with DAAs. Therefore, clinicians should be aware of such risks during and after antiviral treatment with DAAs.
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Affiliation(s)
- Hiroyasu Sakai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Takao Miwa
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Yoshikazu Ikoma
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Tatsunori Hanai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Nobuhiko Nakamura
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Kenji Imai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Junichi Kitagawa
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Yohei Shirakami
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Nobuhiro Kanemura
- Department of Hematology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Atsushi Suetsugu
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Koji Takai
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Makoto Shiraki
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan
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Zhang SL, Chen C, Rao QW, Guo Z, Wang X, Wang ZM, Wang LS. Incidence, Prognostic Factors and Survival Outcome in Patients With Primary Hepatic Lymphoma. Front Oncol 2020; 10:750. [PMID: 32477954 PMCID: PMC7239999 DOI: 10.3389/fonc.2020.00750] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/20/2020] [Indexed: 12/14/2022] Open
Abstract
Aim: The objective of our study was to investigate the epidemiologic characteristics, prognostic factors and survival in patients with primary hepatic lymphoma (PHL). Methods: PHL patients diagnosed between 1983 and 2015 were identified from the SEER database. The temporal trend in PHL incidence was assessed using joinpoint regression software. Overall survival(OS) and disease-specific survival (DSS) was evaluated using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analysis was performed to identify the independent prognostic factors for OS and DSS. Nomograms to predict survival possibilities were constructed based on the identified independent prognostic factors. Results: A total of 1,182 patients were identified with PHL. The mean age was 61.7 ± 17.1 years with a male to female of 1.6:1. Diffuse large B-cell lymphoma (59.8%) was the most common histological subtype. The incidence of PHL steadily increasing by an annual percentage change (APC) of 2.6% (95% CI 2.0-3.2, P < 0.05). The 1-, 5-, and 10-year OS rates were 50.85, 39.6, and 30.4%, respectively, and the corresponding DSS rates were 55.3, 47.9, and 43.3%, respectively. Multivariate Cox regression analysis revealed that age, sex, race, marital status, histological subtype, surgery, and chemotherapy were independent prognostic factors for survival. Nomograms specifically for DLBCL were constructed to predict 1-, 5-, and 10-year OS and DSS possibility, respectively. The concordance index (C-index) and calibration plots showed the established nomograms had robust and accurate performance. Conclusion: PHL were rare but the incidence has been steadily increasing over the past four decades. Survival has improved in recent years. Surgery or chemotherapy could provide better OS and DSS. The established nomograms specifically for DLBCL were robust and accurate in predicting 1-, 5-, and 10-year OS and DSS.
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Affiliation(s)
| | - Chen Chen
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qian-Wen Rao
- Minhang Hospital, Fudan University, Shanghai, China
| | - Zhe Guo
- Department of Internal Medicine, Ophthalmic Hospital of Hebei Province, Xingtai, China
| | - Xin Wang
- Department of Acupuncture and Moxibustion, Central Hospital of Shanghai Xuhui District, Shanghai, China
| | - Zhi-Ming Wang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of Medical Oncology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Li-Shun Wang
- Minhang Hospital, Fudan University, Shanghai, China
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Defrancesco I, Zerbi C, Rattotti S, Merli M, Bruno R, Paulli M, Arcaini L. HCV infection and non-Hodgkin lymphomas: an evolving story. Clin Exp Med 2020; 20:321-328. [PMID: 32052244 DOI: 10.1007/s10238-020-00615-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 02/07/2020] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus infection represents a global health problem with 3% of population infected worldwide. Several epidemiological studies have shown an increased risk of B cell non-Hodgkin lymphomas in HCV-infected subjects with a wide geographic variability. The observation that HCV eradication by antiviral treatment is associated with successful lymphoma response provided the most convincing evidence for the causal role of HCV in lymphoma's development. According to the most accepted model, HCV-driven chronic antigenic stimulation may represent the major stimulus for lymphoma growth. Several evidences have led to recommend antiviral therapy (in the past interferon-based, now the new direct-acting antiviral agents) in the setting of asymptomatic indolent B cell lymphomas not requiring an immediate systemic treatment. The favourable profile of direct-acting antiviral agents supports the HCV eradication also in the setting of HCV-positive diffuse large B cell lymphoma; however, further studies are needed to assess the appropriate timing of these drugs in the treatment of aggressive lymphomas. Multidisciplinary management involving expert hepatologists is highly warranted.
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Affiliation(s)
| | - Caterina Zerbi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Sara Rattotti
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100, Pavia, Italy
| | - Michele Merli
- Division of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi-Azienda Socio-Sanitaria Territoriale Sette Laghi, University of Insubria, Varese, Italy
| | - Raffaele Bruno
- Division of Infectious Diseases Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Department of Medical, Surgical, Diagnostic and Paediatric Science, University of Pavia, Pavia, Italy
| | - Marco Paulli
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,Anatomic Pathology Section, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Luca Arcaini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy. .,Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100, Pavia, Italy.
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Gallo A, Miceli V, Bulati M, Iannolo G, Contino F, Conaldi PG. Viral miRNAs as Active Players and Participants in Tumorigenesis. Cancers (Basel) 2020; 12:358. [PMID: 32033193 PMCID: PMC7072176 DOI: 10.3390/cancers12020358] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/22/2020] [Accepted: 01/31/2020] [Indexed: 02/07/2023] Open
Abstract
The theory that viruses play a role in human cancers is now supported by scientific evidence. In fact, around 12% of human cancers, a leading cause of morbidity and mortality in some regions, are attributed to viral infections. However, the molecular mechanism remains complex to decipher. In recent decades, the uncovering of cellular miRNAs, with their invaluable potential as diagnostic and prognostic biomarkers, has increased the number of studies being conducted regarding human cancer diagnosis. Viruses develop clever mechanisms to succeed in the maintenance of the viral life cycle, and some viruses, especially herpesviruses, encode for miRNA, v-miRNAs. Through this viral miRNA, the viruses are able to manipulate cellular and viral gene expression, driving carcinogenesis and escaping the host innate or adaptive immune system. In this review, we have discussed the main viral miRNAs and virally influenced cellular pathways, and their capability to drive carcinogenesis.
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Affiliation(s)
- Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
| | - Vitale Miceli
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
| | - Matteo Bulati
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
| | - Gioacchin Iannolo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
| | - Flavia Contino
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
- Scienze Mediche Chirurgiche E Sperimentali, Università degli Studi di Sassari, Piazza Universita, 07100 Sassari, Italy
| | - Pier Giulio Conaldi
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90100 Palermo, Italy; (V.M.); (M.B.); (G.I.); (F.C.); (P.G.C.)
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Marrone A, Ciotti M, Rinaldi L, Adinolfi LE, Ghany M. Hepatitis B and C virus infection and risk of haematological malignancies. J Viral Hepat 2020; 27:4-12. [PMID: 31325404 DOI: 10.1111/jvh.13183] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/23/2019] [Accepted: 06/20/2019] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are classified as oncogenic human viruses. Chronic HBV and HCV infections are associated with higher risk of haematological malignancy development. Direct and indirect oncogenic mechanisms have been demonstrated for both HBV and HCV in several studies. HCV and overt/occult HBV infections in patients with oncohaematological disease constitute an impediment and a threat during immunosuppressive chemotherapy treatment. We review the HBV and HCV oncogenic mechanisms and the impact and the safety of antiviral treatment in patients with haematological malignancies.
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Affiliation(s)
- Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marco Ciotti
- Laboratory of Clinical Microbiology and Virology, Polyclinic Tor Vergata Foundation, Rome, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marc Ghany
- Liver Diseases Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USA
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Hepatitis C virus and risk of extrahepatic malignancies: a case-control study. Sci Rep 2019; 9:19444. [PMID: 31857595 PMCID: PMC6923417 DOI: 10.1038/s41598-019-55249-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
Epidemiological studies have demonstrated an increased risk of non-Hodgkin lymphoma (NHL) in patients with chronic hepatitis C virus (HCV) infection. Therefore, we investigated the risk of extrahepatic malignancies associated with HCV infection. Inpatients diagnosed with lymphoma, breast, thyroid, kidney, or pancreatic cancer (research group, n = 17,925) as well as inpatients with no malignancies (control group, n = 16,580) matched by gender and age were enrolled from The First Affiliated Hospital of Nanjing Medical University between January 2008 and December 2016. A case-control study was conducted by retrospective analysis. The difference in HCV prevalence was analyzed between the research group and the control group. Also, the research group was compared to the 2006 National Hepatitis C sero-survey in China. A total of 86 cases were positive for anti-HCV in the research group. Compared with the control group (103 cases were anti-HCV positive), no significant associations between extrahepatic malignancies and HCV infection were observed. Meanwhile, compared to the 2006 National Hepatitis C sero-survey, we observed a significant association between the chronic lymphoma leukemia/small lymphocytic lymphoma (CLL/SLL) and HCV seropositivity in females in the research group aged 1–59 years old (OR = 14.69; 95% CI, 1.94–111.01). HCV infection had a potential association with CLL/SLL in females aged 1–59 years old. Our study did not confirm an association between HCV infection and the risk of extrahepatic malignancies. In regions with a low HCV prevalence, the association between HCV infection and extrahepatic malignancies needs further investigation.
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Abstract
Viral infection is a major contributor to the global cancer burden. Recent advances have revealed that seven known oncogenic viruses promote tumorigenesis through shared host cell targets and pathways. A comprehensive understanding of the principles of viral oncogenesis may enable the identification of unknown infectious aetiologies of cancer and the development of therapeutic or preventive strategies for virus-associated cancers. In this Review, we discuss the molecular mechanisms of viral oncogenesis in humans. We highlight recent advances in understanding how viral manipulation of host cellular signalling, DNA damage responses, immunity and microRNA targets promotes the initiation and development of cancer.
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Affiliation(s)
- Nathan A Krump
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jianxin You
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Immunotherapy in Hepatocellular Carcinoma: Is There a Light at the End of the Tunnel? Cancers (Basel) 2019; 11:cancers11081078. [PMID: 31366113 PMCID: PMC6721326 DOI: 10.3390/cancers11081078] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/10/2019] [Accepted: 07/23/2019] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with dismal prognosis when diagnosed at advanced stages. Surgical resection of the primary tumor or orthotropic liver transplantation serves as a potential curative option. However, this approach is highly dependent on the hepatic reserve and baseline functional status of the patient. Liver directed therapies such as portal vein embolization (PVE), trans-arterial chemoembolization (TACE), and systemic chemotherapy are employed in non-surgical candidates. Sorafenib was the only approved systemic therapeutic agent for almost a decade until the recent approval of lenvatinib by the United States Food and Drug Administration (FDA) as an alternate first-line agent. Regorafenib, nivolumab, pembrolizumab and cabozantinib are approved by the FDA as second-line agents in patients who failed or could not tolerate sorafenib. Ramucirumab was recently FDA approved for the subset of patients that have high alfa-fetoprotein levels (>400 ng/mL). A better understanding of tumorigenesis and encouraging clinical trial results that evaluated immune-checkpoint inhibitors opened doors for immunotherapy in HCC. Immune checkpoint inhibitors have demonstrated a prolonged median overall and progression-free survival in a subset of patients with HCC. On-going translational and clinical research will hopefully provide us with a better understanding of tumor markers, genetic aberrations and other factors that determine the immunotherapy response in HCC. In this review, we sought to summarize the potential role and future directions of immunotherapy in the management of HCC.
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Kuna L, Jakab J, Smolic R, Wu GY, Smolic M. HCV Extrahepatic Manifestations. J Clin Transl Hepatol 2019; 7:172-182. [PMID: 31293918 PMCID: PMC6609844 DOI: 10.14218/jcth.2018.00049] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 02/21/2019] [Accepted: 03/17/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) has been shown to affect many tissues other than liver. However, of the many extrahepatic manifestations (EMs) that have been associated with HCV, including cryoglobulinemia, lymphoma, insulin resistance, type 2 diabetes and neurological disorders, only a few have been shown to be directly related to HCV infection of extrahepatic tissues. HCV-triggered immune-mediated mechanisms account for most of the EMs. It is estimated that up to 74% of patients with chronic hepatitis C can develop at least one EM. All HCV patients with EMs should be considered for antiviral therapy, although not all will resolve with sustained virological response.
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Affiliation(s)
- Lucija Kuna
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Jelena Jakab
- Department of Pathophysiology and Physiology with Immunology, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Internal Medicine, Faculty of Medicine, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - Robert Smolic
- Department of Pathophysiology and Physiology with Immunology, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, Osijek, Croatia
| | - George Y Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, Osijek, Croatia
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