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Sabourin KR, Mugisha J, Asiki G, Nalwoga A, Labo N, Miley W, Beyer R, Rochford R, Johnston TW, Newton R, Whitby D. Epstein-Barr virus (EBV) antibody changes over time in a general population cohort in rural Uganda, 1992-2008. Infect Agent Cancer 2023; 18:55. [PMID: 37775773 PMCID: PMC10543268 DOI: 10.1186/s13027-023-00534-7] [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: 06/28/2023] [Accepted: 09/12/2023] [Indexed: 10/01/2023] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV) infection is ubiquitous and in sub-Saharan Africa, occurs early in life. In a population-based rural African cohort, we leveraged historical samples from the General Population Cohort (GPC) in Uganda to examine the epidemiology of infection with EBV over time, in the era of HIV. METHODS We used 9024 serum samples collected from the GPC in 1992, 2000, 2008, from 7576 participants across the age range (0-99 years of age) and tested for anti-EBV immunoglobulin G (IgG) antibodies to EAd, VCA, and EBNA-1 using a multiplex bead-based assay. The related gammaherpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV) seropositivity was also determined by detection of anti-KSHV IgG antibodies to K8.1 or ORF73 measured by recombinant protein enzyme-linked immunosorbent assay. Data on sex, age, and HIV serostatus were also collected. EBV seropositivity was modeled with age (excluding those under one year, who may have had maternal antibodies), sex, HIV serostatus, and KSHV serostatus using generalized linear mixed effects models to produce beta estimates. RESULTS More than 93% of children were EBV seropositive by one year of age. EBV seropositivity was significantly associated with KSHV seropositivity. Anti-EBNA-1 antibody levels decreased with increasing age and were lower on average in people living with HIV. In general, anti-EAd antibody levels increased with age, were higher in males and KSHV seropositive persons, but decreased over calendar time. Anti-VCA antibody levels increased with age and with calendar time and were higher in KSHV seropositive persons but lower in males. CONCLUSIONS This is the first study to identify factors associated with EBV antibodies across the entire life-course in rural sub-Saharan Africa. Consistent with other studies, EBV was near ubiquitous in the population by age one year. Patterns of antibodies show changes by age, sex and calendar time, but no association with HIV was evident, suggesting no relationship between EBV sero-epidemiology and the spread of HIV in the population over time in Uganda.
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Affiliation(s)
- Katherine R Sabourin
- Department of Immunology and Microbiology, CU School of Medicine, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, RC1N P18-9403D, Aurora, CO, 80045, USA.
- UK Medical Research Council/ Uganda Virus Research Institute and London School of Health and Tropical Medicine Uganda Research Unit, Entebbe, Uganda.
| | - Joseph Mugisha
- UK Medical Research Council/ Uganda Virus Research Institute and London School of Health and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Gershim Asiki
- UK Medical Research Council/ Uganda Virus Research Institute and London School of Health and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
- The African Population and Health Research Center, Nairobi, Kenya
| | - Angela Nalwoga
- Department of Immunology and Microbiology, CU School of Medicine, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, RC1N P18-9403D, Aurora, CO, 80045, USA
- UK Medical Research Council/ Uganda Virus Research Institute and London School of Health and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Nazzarena Labo
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Wendell Miley
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Rachel Beyer
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Rosemary Rochford
- Department of Immunology and Microbiology, CU School of Medicine, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, RC1N P18-9403D, Aurora, CO, 80045, USA
| | | | - Robert Newton
- UK Medical Research Council/ Uganda Virus Research Institute and London School of Health and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
- University of York, York, UK
| | - Denise Whitby
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
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Du Y, Yu X, Chang ET, Yin L, Lian S, Wu B, Li F, Liang Z, Zeng Y, Chu B, Wei K, Zhan J, Liang X, Ye W, Ji M. EBV antibody and gastric cancer risk: a population-based nested case-control study in southern China. BMC Cancer 2023; 23:521. [PMID: 37291490 DOI: 10.1186/s12885-023-10994-0] [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: 10/30/2022] [Accepted: 05/22/2023] [Indexed: 06/10/2023] Open
Abstract
BACKGROUND We aim to clarify the controversial associations between EBV-related antibodies and gastric cancer risk. METHODS We analysed the associations between serological Epstein-Barr nuclear antigen 1 immunoglobulin A (EBNA1-IgA) and viral capsid antigen immunoglobulin A (VCA-IgA) by enzyme-linked immunosorbent assay and the risk of gastric cancer in a nested case-control study originated from a population-based nasopharyngeal carcinoma (NPC) screening cohort in Zhongshan, a city of southern China, including 18 gastric cancer cases and 444 controls. Conditional logistic regression was used to calculate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs). RESULTS All the sera of cases were sampled before diagnosis and the median time interval was 3.04 (range: 0.04, 7.59) years. Both increased relative optical density (rOD) values of EBNA1-IgA and VCA-IgA were associated with higher risks of gastric cancer with age adjusted ORs of 1.99 (95%CI: 1.07, 3.70) and 2.64 (95%CI: 1.33, 5.23), respectively. Each participant was further classified as high or medium/low risk based on a combination of two anti-EBV antibody levels. Participants in the high-risk group had substantially higher odds of developing gastric cancer than that in the medium/low risk group with an age adjusted OR of 6.53 (95%CI: 1.69, 25.26). CONCLUSIONS Our research reveals positive associations between EBNA1-IgA and VCA-IgA and gastric cancer risk in southern China. We thus postulate that EBNA1-IgA and VCA-IgA might appear to be potential biomarkers for gastric cancer. More research to further validate the results among diverse populations and investigate its underlying biological mechanism is needed.
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Affiliation(s)
- Yun Du
- Zhongshan City People's Hospital, Cancer Research Institute of Zhongshan City, Zhongshan, 528400, People's Republic of China
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Xia Yu
- Zhongshan City People's Hospital, Cancer Research Institute of Zhongshan City, Zhongshan, 528400, People's Republic of China
| | - Ellen T Chang
- Center for Health Sciences, Exponent, Inc, Menlo Park, CA, 94025, USA
| | - Li Yin
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Shifeng Lian
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Biaohua Wu
- Zhongshan City People's Hospital, Cancer Research Institute of Zhongshan City, Zhongshan, 528400, People's Republic of China
| | - Fugui Li
- Zhongshan City People's Hospital, Cancer Research Institute of Zhongshan City, Zhongshan, 528400, People's Republic of China
| | - Zhiheng Liang
- Zhongshan City People's Hospital, Cancer Research Institute of Zhongshan City, Zhongshan, 528400, People's Republic of China
| | - Yumei Zeng
- Department of Pathology, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Bing Chu
- Department of Pathology, Zhongshan City People's Hospital, Zhongshan, 528400, People's Republic of China
| | - Kuangrong Wei
- Zhongshan City People's Hospital, Cancer Research Institute of Zhongshan City, Zhongshan, 528400, People's Republic of China
| | - Jiyun Zhan
- Xiaolan Public Health Service Center, Zhongshan, 528400, People's Republic of China
| | - Xuejun Liang
- Xiaolan Public Health Service Center, Zhongshan, 528400, People's Republic of China
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden.
| | - Mingfang Ji
- Zhongshan City People's Hospital, Cancer Research Institute of Zhongshan City, Zhongshan, 528400, People's Republic of China.
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Tan H, Gong Y, Liu Y, Long J, Luo Q, Faleti OD, Lyu X. Advancing therapeutic strategies for Epstein-Barr virus-associated malignancies through lytic reactivation. Biomed Pharmacother 2023; 164:114916. [PMID: 37229802 DOI: 10.1016/j.biopha.2023.114916] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023] Open
Abstract
Epstein-Barr virus (EBV) is a widespread human herpes virus associated with lymphomas and epithelial cell cancers. It establishes two separate infection phases, latent and lytic, in the host. Upon infection of a new host cell, the virus activates several pathways, to induce the expression of lytic EBV antigens and the production of infectious virus particles. Although the carcinogenic role of latent EBV infection has been established, recent research suggests that lytic reactivation also plays a significant role in carcinogenesis. In this review, we summarize the mechanism of EBV reactivation and recent findings about the role of viral lytic antigens in tumor formation. In addition, we discuss the treatment of EBV-associated tumors with lytic activators and the targets that may be therapeutically effective in the future.
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Affiliation(s)
- Haiqi Tan
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Yibing Gong
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Yi Liu
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Jingyi Long
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Qingshuang Luo
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Oluwasijibomi Damola Faleti
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, 999000, Hong Kong Special Administrative Region of China
| | - Xiaoming Lyu
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China.
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Xie C, Zhong LY, Bu GL, Zhao GX, Yuan BY, Liu YT, Sun C, Zeng MS. Anti-EBV antibodies: Roles in diagnosis, pathogenesis, and antiviral therapy. J Med Virol 2023; 95:e28793. [PMID: 37212266 DOI: 10.1002/jmv.28793] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/02/2023] [Accepted: 05/03/2023] [Indexed: 05/23/2023]
Abstract
Epstein-Barr virus (EBV) infection is prevalent in global population and associated with multiple malignancies and autoimmune diseases. During the infection, EBV-harbored or infected cell-expressing antigen could elicit a variety of antibodies with significant role in viral host response and pathogenesis. These antibodies have been extensively evaluated and found to be valuable in predicting disease diagnosis and prognosis, exploring disease mechanisms, and developing antiviral agents. In this review, we discuss the versatile roles of EBV antibodies as important biomarkers for EBV-related diseases, potential driving factors of autoimmunity, and promising therapeutic agents for viral infection and pathogenesis.
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Affiliation(s)
- Chu Xie
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Lan-Yi Zhong
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Guo-Long Bu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Ge-Xin Zhao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Bo-Yu Yuan
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Yuan-Tao Liu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Cong Sun
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Guangzhou, China
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Zhang Y, Zhang Q, Xu L, Wang W, Xiao H, Luo B. Analysis of the relationship between the expression of EBV-related antibodies and ET-1 axis in gastric cancer. Cancer Biomark 2022; 35:321-329. [DOI: 10.3233/cbm-220001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND AND OBJECTIVE: EBV-associated gastric cancer (EBVaGC) is a distinct subtype of GC, and EBV plays an important role in tumor progress. The standard method to identify EBV-positive tumor is determined by in situ hybridization for EBV-encoded EBERs in tumor tissues. The present study aims to detect the serological expression of EBV-related antibodies and ET-1 axis to provide a noninvasive method for diagnosis of EBVaGC. METHODS: The content of EBV-related antibodies and ET-1 axis in preoperative peripheral blood of GC was performed by Chemiluminescence and ELISA assay. The EBV DNA copy number was measured by qRT-PCR. RESULTS: The results showed that the levels of anti-EBV early antigen (EA) IgG, viral capsid antigen (VCA) IgA, nuclear antigen (NA) IgG, and EBV DNA copy number were significantly higher in EBVaGC. The ET-1 axis level was much lower in EBVaGC than EBVnGC. CONCLUSIONS: The combined detection of specific anti-EBV antibodies and ET-1 axis might provide new molecular markers for the identification of EBVaGC.
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Affiliation(s)
- Yan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Laboratory, Zibo Central Hospital, Zibo, Shandong, China
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Qianqian Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Lin Xu
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong, China
| | - Weiwen Wang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Hua Xiao
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
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Clinicopathological features of Epstein-Barr virus-associated superficial early stage gastric cancer treated with endoscopic submucosal dissection. Dig Liver Dis 2022; 54:946-953. [PMID: 34535407 DOI: 10.1016/j.dld.2021.08.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Epstein-Barr virus (EBV) is known to be involved in gastric carcinogenesis. EBV-associated early gastric carcinoma (EBVEGC) has a lower incidence of lymph node involvement and could be an expanded indication for endoscopic submucosal dissection (ESD) treatment. AIM To clarify the prevalence and clinicopathological features of EBVEGC. METHODS This study reviewed 618 lesions in 519 patients treated with ESD between 2014 and 2016. Tissue microarray sections were subjected to in situ hybridization staining for EBV-encoded small RNA transcripts (EBER). Lesions positive for EBER were compared with control lesions and were retrospectively analyzed. RESULTS 12 (1.9%) of the 618 lesions were EBVEGC. EBVEGCs were more frequently located near the atrophic border than control lesions in the middle or upper stomach and were reddish. EBVEGC invasion was deeper and more often histologically undifferentiated. On narrow-band imaging magnifying endoscopy, the EBVEGC group significantly more often showed an endoscopic lace pattern, defined as an absent or obscure microsurface pattern and a microvascular pattern of a tiny, dense, and irregular subepithelial capillary network. The rate of curative resection was significantly lower in the EBVEGC group. CONCLUSIONS Only 1.9% of the ESD specimens were EBV-positive. Endoscopic features could raise clinical suspicion of EBV infection.
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Escalante GM, Mutsvunguma LZ, Muniraju M, Rodriguez E, Ogembo JG. Four Decades of Prophylactic EBV Vaccine Research: A Systematic Review and Historical Perspective. Front Immunol 2022; 13:867918. [PMID: 35493498 PMCID: PMC9047024 DOI: 10.3389/fimmu.2022.867918] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/11/2022] [Indexed: 02/06/2023] Open
Abstract
BackgroundEpstein-Barr virus (EBV) is the causal agent of infectious mononucleosis and has been associated with various cancers and autoimmune diseases. Despite decades of research efforts to combat this major global health burden, there is no approved prophylactic vaccine against EBV. To facilitate the rational design and assessment of an effective vaccine, we systematically reviewed pre-clinical and clinical prophylactic EBV vaccine studies to determine the antigens, delivery platforms, and animal models used in these studies.MethodsWe searched Cochrane Library, ClinicalTrials.gov, Embase, PubMed, Scopus, Web of Science, WHO’s Global Index Medicus, and Google Scholar from inception to June 20, 2020, for EBV prophylactic vaccine studies focused on humoral immunity.ResultsThe search yielded 5,614 unique studies. 36 pre-clinical and 4 clinical studies were included in the analysis after screening against the exclusion criteria. In pre-clinical studies, gp350 was the most commonly used immunogen (33 studies), vaccines were most commonly delivered as monomeric proteins (12 studies), and mice were the most used animal model to test immunogenicity (15 studies). According to an adaptation of the CAMARADES checklist, 4 pre-clinical studies were rated as very high, 5 as high, 13 as moderate quality, 11 as poor, and 3 as very poor. In clinical studies, gp350 was the sole vaccine antigen, delivered in a vaccinia platform (1 study) or as a monomeric protein (3 studies). The present study was registered in PROSPERO (CRD42020198440).ConclusionsFour major obstacles have prevented the development of an effective prophylactic EBV vaccine: undefined correlates of immune protection, lack of knowledge regarding the ideal EBV antigen(s) for vaccination, lack of an appropriate animal model to test vaccine efficacy, and lack of knowledge regarding the ideal vaccine delivery platform. Our analysis supports a multivalent antigenic approach including two or more of the five main glycoproteins involved in viral entry (gp350, gB, gH/gL, gp42) and a multimeric approach to present these antigens. We anticipate that the application of two underused challenge models, rhesus macaques susceptible to rhesus lymphocryptovirus (an EBV homolog) and common marmosets, will permit the establishment of in vivo correlates of immune protection and attainment of more generalizable data.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=198440, identifier PROSPERO I.D. CRD4202019844.
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Identification of anti-Epstein-Barr virus (EBV) antibody signature in EBV-associated gastric carcinoma. Gastric Cancer 2021; 24:858-867. [PMID: 33661412 PMCID: PMC8206016 DOI: 10.1007/s10120-021-01170-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 02/09/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Around 10% of gastric carcinomas (GC) contain Epstein-Barr virus (EBV) DNA. We characterized the GC-specific antibody response to this common infection, which may provide a noninvasive method to detect EBV-positive GC and elucidate its contribution to carcinogenesis. METHODS Plasma samples from EBV-positive (n = 28) and EBV-negative (n = 34) Latvian GC patients were immune-profiled against 85 EBV proteins on a multi-microbial Nucleic Acid Programmable Protein Array (EBV-NAPPA). Antibody responses were normalized for each sample as ratios to the median signal intensity (MNI) across all antigens, with seropositivity defined as MNI ≥ 2. Antibodies with ≥ 20% sensitivity at 95% specificity for tumor EBV status were verified by enzyme-linked immunosorbent assay (ELISA) and validated in independent samples from Korea and Poland (n = 24 EBV-positive, n = 65 EBV-negative). RESULTS Forty anti-EBV IgG and eight IgA antibodies were detected by EBV-NAPPA in ≥ 10% of EBV-positive or EBV-negative GC patients, of which nine IgG antibodies were discriminative for tumor EBV status. Eight of these nine were verified and seven were validated by ELISA: anti-LF2 (odds ratio = 110.0), anti-BORF2 (54.2), anti-BALF2 (44.1), anti-BaRF1 (26.7), anti-BXLF1 (12.8), anti-BRLF1 (8.3), and anti-BLLF3 (5.4). The top three had areas under receiver operating characteristics curves of 0.81-0.85 for distinguishing tumor EBV status. CONCLUSIONS The EBV-associated GC-specific humoral response was exclusively directed against lytic cycle immediate-early and early antigens, unlike other EBV-associated malignancies such as nasopharyngeal carcinoma and lymphoma where humoral response is primarily directed against late lytic antigens. Specific anti-EBV antibodies could have utility for clinical diagnosis, epidemiologic studies, and immune-based precision treatment of EBV-positive GC.
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Torres K, Landeros N, Wichmann IA, Polakovicova I, Aguayo F, Corvalan AH. EBV miR-BARTs and human lncRNAs: Shifting the balance in competing endogenous RNA networks in EBV-associated gastric cancer. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166049. [PMID: 33401001 DOI: 10.1016/j.bbadis.2020.166049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 12/04/2020] [Accepted: 12/14/2020] [Indexed: 02/06/2023]
Abstract
Non-coding RNAs (ncRNAs) contribute to the regulation of gene expression. By acting as competing endogenous RNA (ceRNA), long non-coding RNAs (lncRNAs) hijack microRNAs (miRNAs) and inhibit their ability to bind their coding targets. Viral miRNAs can compete with and target the same transcripts as human miRNAs, shifting the balance in networks associated with multiple cellular processes and diseases. Epstein-Barr virus (EBV) is an example of how a subset of viral coding RNA and non-coding RNAs can cause deregulation of human transcripts and contribute to the development of EBV-associated malignancies. EBV non-coding transforming genes include lncRNAs (i.e circular RNAs), and small ncRNAs (i.e. miRNAs). Among the latter, most ongoing research has focused on miR-BARTs whereas target many genes associated with apoptosis and epithelial-mesenchymal transition, in EBV-associated gastric cancer (GC). In this review, we propose to include the interactions between EBV ncRNAs human transcripts in the hypothesis known as "competitive viral and host RNAs". These interactions may shift the balance in biological pathways such as apoptosis and epithelial-mesenchymal transition in EBV-associated gastric cancer.
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Affiliation(s)
- Keila Torres
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile; UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Natalia Landeros
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile; UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ignacio A Wichmann
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile; UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Iva Polakovicova
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile; UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francisco Aguayo
- Advanced Center for Chronic Diseases, Universidad de Chile, Santiago, Chile; Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Alejandro H Corvalan
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile; UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Ignatova E, Seriak D, Fedyanin M, Tryakin A, Pokataev I, Menshikova S, Vakhabova Y, Smirnova K, Tjulandin S, Ajani JA. Epstein-Barr virus-associated gastric cancer: disease that requires special approach. Gastric Cancer 2020; 23:951-960. [PMID: 32514646 DOI: 10.1007/s10120-020-01095-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
Epstein-Barr virus-associated gastric cancer [EBV-associated GC, EBV( +) GC] is a distinct molecular subtype of gastrointestinal (GI) cancers. It accounts for up to 10% of all molecular subtypes of gastric cancer (GC). It has unique genetic and epigenetic features, which determine its definitive phenotype with male and younger age predominance, proximal stomach localization, and diffuse adenocarcinoma histology. EBV( +) GC also has a unique epigenetic profile and mutational status with frequent mutations of PIK3CA, ARID1A and BCOR, and PD-L1 and PD-L2 amplifications, as well. The aim of this review is to highlight clinical significance of EBV( +) GC and prognostic role of EBV infection, and to determine potentially appropriate drug therapy for this disease.
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Affiliation(s)
- Ekaterina Ignatova
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation.
| | - Daria Seriak
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation
| | - Mikhail Fedyanin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Alexey Tryakin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Ilya Pokataev
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Sofia Menshikova
- Department of Anticancer Drug Treatment, AO K31 City, Moscow, Russian Federation
| | - Yuliya Vakhabova
- Chemotherapy Department of Tumors Drug Treatment, Moscow Scientific Research Oncological Institution N.a. P.A. Herzen, Branch of Federal State Budgetary Institution "National Medical Research Center of Radiology" of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
| | - Ksenia Smirnova
- Laboratory of Viral Carcinogenesis, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
| | - Sergey Tjulandin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
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11
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Morales-Sánchez A, Torres J, Cardenas-Mondragón MG, Romo-González C, Camorlinga-Ponce M, Flores-Luna L, Fuentes-Pananá EM. Detection of Epstein-Barr Virus DNA in Gastric Biopsies of Pediatric Patients with Dyspepsia. Pathogens 2020; 9:pathogens9080623. [PMID: 32751557 PMCID: PMC7459453 DOI: 10.3390/pathogens9080623] [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: 05/27/2020] [Revised: 07/25/2020] [Accepted: 07/27/2020] [Indexed: 12/21/2022] Open
Abstract
In this study, we assessed the presence of Epstein-Barr virus (EBV) in gastric samples derived from pediatric patients with dyspeptic symptoms, aiming to understand whether EBV participates in the development of early gastric lesions influencing chronic inflammation, in conjunction with the Helicobacter pylori (Hp) bacterium. We analyzed EBV load in 236 gastric biopsies derived from 186 pediatric patients with chronic dyspepsia and compared it with EBV serology, Hp load and serology, and with immune cell infiltration. We found that 7.5% of patients were positive for EBV load, ranging from 240 to 29,685 genomic copies/μg of DNA. Hp genomic sequences were found in 24.7% of patients. EBV positive samples did not correlate with Hp status and were characterized by absent to moderate immune cell infiltration. To our knowledge, this is the first study addressing EBV load in the stomach in a large cohort of pediatric patients with dyspeptic symptoms, providing evidence of EBV localization in the gastric mucosa in early inflammatory lesions. The lack of correlation between EBV and both Hp infection and inflammation is perhaps explained by independent pathogenic mechanisms or because of the randomness of the gastritis sampling. This is also supported by a moderate association between EBV load and serology.
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Affiliation(s)
- Abigail Morales-Sánchez
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gomez, Mexico City 06720, Mexico;
| | - Javier Torres
- Infectious Diseases Research Unit, CMNS-XXI, Mexican Institute of Social Security (IMSS), Mexico City 06720, Mexico; (J.T.); (M.G.C.-M.); (M.C.-P.)
| | - María G. Cardenas-Mondragón
- Infectious Diseases Research Unit, CMNS-XXI, Mexican Institute of Social Security (IMSS), Mexico City 06720, Mexico; (J.T.); (M.G.C.-M.); (M.C.-P.)
| | - Carolina Romo-González
- Laboratory of Experimental Bacteriology, National Institute of Pediatrics, Mexico City 04530, Mexico;
| | - Margarita Camorlinga-Ponce
- Infectious Diseases Research Unit, CMNS-XXI, Mexican Institute of Social Security (IMSS), Mexico City 06720, Mexico; (J.T.); (M.G.C.-M.); (M.C.-P.)
| | - Lourdes Flores-Luna
- Research Center in Population Health, National Institute of Public Health, Cuernavaca 62100, Mexico;
| | - Ezequiel M. Fuentes-Pananá
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gomez, Mexico City 06720, Mexico;
- Correspondence:
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12
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Bakkalci D, Jia Y, Winter JR, Lewis JE, Taylor GS, Stagg HR. Risk factors for Epstein Barr virus-associated cancers: a systematic review, critical appraisal, and mapping of the epidemiological evidence. J Glob Health 2020; 10:010405. [PMID: 32257153 PMCID: PMC7125417 DOI: 10.7189/jogh.10.010405] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Epstein Barr Virus (EBV) infects 90%-95% of all adults globally and causes ~ 1% of all cancers. Differing proportions of Burkitt's lymphoma (BL), gastric carcinoma (GC), Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC) are associated with EBV. We sought to systematically review the global epidemiological evidence for risk factors that (in addition to EBV) contribute to the development of the EBV-associated forms of these cancers, assess the quality of the evidence, and compare and contrast the cancers. METHODS MEDLINE, Embase and Web of Science were searched for studies of risk factors for EBV-associated BL, GC, HL and NPC without language or temporal restrictions. Studies were excluded if there was no cancer-free comparator group or where analyses of risk factors were inadequately documented. After screening and reference list searching, data were extracted into standardised spreadsheets and quality assessed. Due to heterogeneity, a narrative synthesis was undertaken. RESULTS 9916 hits were retrieved. 271 papers were retained: two BL, 24 HL, one GC and 244 NPC. The majority of studies were from China, North America and Western Europe. Risk factors were categorised as dietary, environmental/non-dietary, human genetic, and infection and clinical. Anti-EBV antibody load was associated with EBV-associated GC and BL. Although the evidence could be inconsistent, HLA-A alleles, smoking, infectious mononucleosis and potentially other infections were risk factors for EBV-associated HL. Rancid dairy products; anti-EBV antibody and EBV DNA load; history of chronic ear, nose and/or throat conditions; herbal medicine use; family history; and human genetics were risk factors for NPC. Fresh fruit and vegetable and tea consumption may be protective against NPC. CONCLUSIONS Many epidemiological studies of risk factors in addition to EBV for the EBV-associated forms of BL, GC, HL and NPC have been undertaken, but there is a dearth of evidence for GC and BL. Available evidence is of variable quality. The aetiology of EBV-associated cancers likely results from a complex intersection of genetic, clinical, environmental and dietary factors, which is difficult to assess with observational studies. Large, carefully designed, studies need to be strategically undertaken to harmonise and clarify the evidence. REGISTRATION PROSPERO CRD42017059806.
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Affiliation(s)
- Deniz Bakkalci
- Institute for Global Health, University College London, London, UK
- Joint first authors, listed alphabetically
| | - Yumeng Jia
- Department of Infectious Disease Epidemiology, Imperial College London, London, UK
- Joint first authors, listed alphabetically
| | - Joanne R Winter
- Institute for Global Health, University College London, London, UK
- Joint first authors, listed alphabetically
| | - Joanna Ea Lewis
- MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, UK
| | - Graham S Taylor
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- Joint senior authors
| | - Helen R Stagg
- Institute for Global Health, University College London, London, UK
- Usher Institute, University of Edinburgh, Edinburgh, UK
- Joint senior authors
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13
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Osumi H, Kawachi H, Yoshio T, Fujisaki J. Clinical impact of Epstein-Barr virus status on the incidence of lymph node metastasis in early gastric cancer. Dig Endosc 2020; 32:316-322. [PMID: 31762090 DOI: 10.1111/den.13584] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 11/20/2019] [Indexed: 02/08/2023]
Abstract
Epstein-Barr virus-positive gastric cancer (EBVGC) comprises approximately 9% of all gastric cancers and is associated with a low prevalence of lymph node metastasis (LNM). Given that limited data concerning LNM in EBV-related early GC are available, EBV status is not considered an indicator for endoscopic submucosal dissection (ESD). In this review, we focused on pT1 EBVGC and on gastric carcinoma with lymphoid stroma (GCLS), and discuss expanded ESD indications and curative resection criteria. In pT1b EBVGC, the incidence of LNM was low (6/180 patients, 3.3%; 95% confidence interval [CI] 1.2-7.1), especially in lymphovascular invasion-negative EBVGC (1/109 patients, 0.9%). No patients with pT1a EBVGC had LNM (0/38 patients, 0%; 95% CI 0-7.6), even those who did not meet the current curative ESD criteria. Although the frequency of LNM in GCLS was low (5.0-10.6%), the incidence of LNM in non-EBV GCLS was relatively high (10.0-20.0%); therefore, EBV status can be considered a more important factor than GCLS. In summary, the clinicopathological characteristics of EBVGC differ from those of conventional GC, and EBV negativity is a risk factor for LNM in early GC. Therefore, patients in this group are likely to be promising candidates for ESD, and we recommend that EBV status evaluation be included in early GC treatment guidelines.
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Affiliation(s)
- Hiroki Osumi
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
| | - Hiroshi Kawachi
- Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
| | - Toshiyuki Yoshio
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
| | - Junko Fujisaki
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
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14
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Camargo MC, Kim KM, Matsuo K, Torres J, Liao LM, Morgan D, Michel A, Waterboer T, Song M, Gulley ML, Dominguez RL, Yatabe Y, Kim S, Cortes-Martinez G, Lissowska J, Zabaleta J, Pawlita M, Rabkin CS. Circulating Antibodies against Epstein-Barr Virus (EBV) and p53 in EBV-Positive and -Negative Gastric Cancer. Cancer Epidemiol Biomarkers Prev 2020; 29:414-419. [PMID: 31719065 PMCID: PMC8272980 DOI: 10.1158/1055-9965.epi-19-0790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 10/01/2019] [Accepted: 11/04/2019] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV)-positive gastric cancers have clinicopathologic differences from EBV-negative tumors and lack TP53 mutation. Serologic profiles may inform viral contribution to carcinogenesis. METHODS We compared humoral responses of EBV-positive (n = 67) and EBV-negative (n = 137) patients with gastric cancer from the International EBV-Gastric Cancer Consortium. Serum antibodies against four EBV proteins, nuclear (EBNA), viral capsid (VCA), early-diffuse (EA-D), and Zta replication activator (ZEBRA), and to p53 were assessed by multiplex assays. OR of antibody level tertiles (T1-T3) were adjusted by logistic regression. We also conducted a meta-analysis of reported anti-p53 seropositivity in gastric cancer. RESULTS Consistent with EBV's ubiquity, 99% of patients were seropositive for anti-EBNA and 98% for anti-VCA, without difference by tumor EBV status. Seropositivity varied between patients with EBV-positive and EBV-negative tumors for anti-EA-D (97% vs. 67%, respectively, P < 0.001) and anti-ZEBRA (97% vs. 85%, respectively, P = 0.009). Adjusted ORs (vs. T1) for patients with EBV-positive versus EBV-negative tumors were significantly elevated for higher antibodies against EBNA (2.6 for T2 and 13 for T3), VCA (1.8 for T2 and 2.4 for T3), EA-D (6.0 for T2 and 44 for T3), and ZEBRA (4.6 for T2 and 12 for T3). Antibodies to p53 were inversely associated with EBV positivity (3% vs. 15%; adjusted OR = 0.16, P = 0.021). Anti-p53 prevalence from the literature was 15%. CONCLUSIONS These serologic patterns suggest viral reactivation in EBV-positive cancers and identify variation of p53 seropositivity by subtype. IMPACT Anti-EBV and anti-p53 antibodies are differentially associated with tumor EBV positivity. Serology may identify EBV-positive gastric cancer for targeted therapies.
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Affiliation(s)
- M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
| | - Kyoung-Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center, Nagoya, Japan
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, CMN SXXI, Instituto Mexicano del Seguro Social, México City, México
| | - Linda M Liao
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Douglas Morgan
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee
- Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama
| | - Angelika Michel
- Infections and Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Minkyo Song
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina
| | - Ricardo L Dominguez
- Department of Medicine, Western Regional Hospital, Santa Rosa de Copan, Honduras
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gustavo Cortes-Martinez
- Servicio de Cirugía, Hospital de Oncología, CMN SXXI, Instituto Mexicano del Seguro Social, México City, México
| | - Jolanta Lissowska
- Division of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Jovanny Zabaleta
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Michael Pawlita
- Infections and Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
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15
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Wells MJ, Jacobson S, Levine PH. An evaluation of HHV-6 as an etiologic agent in Hodgkin lymphoma and brain cancer using IARC criteria for oncogenicity. Infect Agent Cancer 2019; 14:31. [PMID: 31709003 PMCID: PMC6833260 DOI: 10.1186/s13027-019-0248-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 09/26/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Human herpesvirus-6 (HHV-6) is a ubiquitous double-stranded DNA virus that can cause roseola infantum, encephalitis, and seizure disorders. Several studies have shown an association between HHV-6 and cancer but confirmation of an etiologic role is lacking. We reviewed the criteria for viral causation of cancer used by The International Agency for Research on Cancer (IARC) for six oncogenic viruses and applied criteria to published reports of HHV-6 and its association with Hodgkin lymphoma and brain tumors. METHODS Our major criteria for oncogenicity were finding evidence of the virus in every tumor cell and prevention of the tumor by an antiviral vaccine. Our six minor criteria included: 1) suggestive serologic correlation, such as higher virus antibody levels in cases compared to controls; 2) evidence of the virus in some but not all tumor cells, and 3) time space clustering. We focused on Epstein-Barr virus (EBV) as the primary virus for comparison as HHV-6 and EBV are both Herpesviridae, ubiquitous infections, and EBV is well-accepted as a human oncovirus. Particular attention was given to Hodgkin lymphoma (HL) and brain cancer as these malignancies have been the most studied. RESULTS No studies reported HHV-6 satisfying either of the major criteria for oncogenicity. Of the minor criteria used by IARC, serologic studies have been paramount in supporting EBV as an oncogenic agent in all EBV-associated tumors, but not for HHV-6 in HL or brain cancer. Clustering of cases was suggestive for both HL and brain cancer and medical intervention suggested by longer survival in patients treated with antiviral agents was reported for brain cancer. CONCLUSION There is insufficient evidence to indicate HHV-6 is an etiologic agent with respect to HL and brain cancers. We suggest that methods demonstrating EBV oncogenicity be applied to HHV-6. It is important that one study has found HHV-6 in all cancer cells in oral cancer in a region with elevated HHV-6 antibodies and therefore HHV-6 can still be considered a possible human oncogenic virus.
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Affiliation(s)
- Michael J. Wells
- School of Community and Population Health, University of New England, 716 Stevens Ave, Portland, ME 04103 USA
| | - Steven Jacobson
- National Institutes of Health, National Institute of Neurological Disorders and Stroke, Viral Immunology Section, 9000 Rockville Pike, Bethesda, MD 20892 USA
| | - Paul H. Levine
- College of Public Health, University of Nebraska, 984355 Medical Center, Omaha, NE 68198 USA
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16
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Epstein Barr virus antibody reactivity and gastric cancer: A population-based case-control study. Cancer Epidemiol 2019; 61:79-88. [PMID: 31154081 DOI: 10.1016/j.canep.2019.05.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 05/14/2019] [Accepted: 05/17/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND In contrast to the recognized role of Helicobacter pylori in the etiology of non-cardia gastric cancer (GC), there is still insufficient epidemiological evidence for the involvement of Epstein-Barr virus (EBV) in gastric carcinogenesis. We aimed to evaluate the relation of antibody profile and antibody reactivity intensity against four individual EBV proteins to GC risk. METHODS We used information from 281 GC cases and 2071 age and sex frequency matched controls recruited in the frame of the MCC-Spain multicase-control study, between 2008 and 2013. Sociodemographic, lifestyle and environmental factors were assessed in face-to-face interviews. Antibody responses to four EBV proteins (EBNA-1, ZEBRA, EA-D, and VCA-p18) were analyzed by multiplex serology. Odds ratios (OR) and 95% confidence intervals were calculated by using logistic regression mixed models to evaluate the association of seropositivity and antibody reactivity against EBV proteins with GC, adjusting for GC risk factors. Stratified analyses by tumor location (cardia vs. non-cardia) and morphology (intestinal vs. diffuse) were done. RESULTS Among controls, seropositivity for EA-D, ZEBRA, EBNA-1 and VCA-p18 was 85%, 91%, 97% and 99%, respectively. Even though seropositivity for none of the studied proteins was associated with a higher GC risk, increasing antibody reactivity against EBNA-1 and VCA-p18 was associated with higher OR of GC. This association was present for cardia and non-cardia cancer cases, and for intestinal and diffuse types. CONCLUSION Our results support the hypothesis that EBV may play a role in GC etiology, and highlight the importance of evaluating specific antibodies and the dose-response relations when studying widespread infections.
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17
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Wang J, Zheng X, Qin Z, Wei L, Lu Y, Peng Q, Gao Y, Zhang X, Zhang X, Li Z, Fu Y, Liu P, Liu C, Yan Q, Xiong W, Li G, Lu J, Ma J. Epstein-Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer. J Biol Chem 2019; 294:4854-4866. [PMID: 30674552 DOI: 10.1074/jbc.ra118.006853] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 01/14/2019] [Indexed: 12/25/2022] Open
Abstract
Epstein-Barr virus-associated gastric cancer (EBVaGC) accounts for about 10% of all gastric cancer cases and has unique pathological and molecular characteristics. EBV encodes a large number of microRNAs, which actively participate in the development of EBV-related tumors. Here, we report that EBV-miR-BART3-3p (BART3-3p) promotes gastric cancer cell growth in vitro and in vivo Moreover, BART3-3p inhibits the senescence of gastric cancer cells induced by an oncogene (RASG12V) or chemotherapy (irinotecan). LMP1 and EBNA3C encoded by EBV have also been reported to have antisenescence effects; however, in EBVaGC specimens, LMP1 expression is very low, and EBNA3C is not expressed. BART3-3p inhibits senescence of gastric cancer cells in a nude mouse model and inhibits the infiltration of natural killer cells and macrophages in tumor by altering the senescence-associated secretory phenotype (SASP). Mechanistically, BART3-3p directly targeted the tumor suppressor gene TP53 and caused down-regulation of p53's downstream target, p21. Analysis from clinical EBVaGC samples also showed a negative correlation between BART3-3p and TP53 expression. It is well known that mutant oncogene RASG12V or chemotherapeutic drugs can induce senescence, and here we show that both RASG12V and a chemotherapy drug also can induce BART3-3p expression in EBV-positive gastric cancer cells, forming a feedback loop that keeps the EBVaGC senescence at a low level. Our results suggest that, although TP53 is seldom mutated in EBVaGC, its expression is finely regulated such that EBV-encoded BART3-3p may play an important role by inhibiting the senescence of gastric cancer cells.
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Affiliation(s)
- Jia Wang
- From the Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.,Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China.,Department of Immunology, Changzhi Medical College, Changzhi, Shanxi 046000, China
| | - Xiang Zheng
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China.,Hunan Key Laboratory of Translational Radiation Oncology, Changsha 410013, China
| | - Zailong Qin
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Changsha 410013, China
| | - Lingyu Wei
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China.,National Health Commission Key Laboratory of Carcinogenesis (Central South University), Changsha 410078, China
| | - Yuanjun Lu
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha 410078, China, and
| | - Qiu Peng
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China
| | - Yingxue Gao
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China
| | - Xuemei Zhang
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China
| | - Xiaoyue Zhang
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China
| | - Zhengshuo Li
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China
| | - Yuxin Fu
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China
| | - Peishan Liu
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China
| | - Can Liu
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China
| | - Qun Yan
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Wei Xiong
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China.,National Health Commission Key Laboratory of Carcinogenesis (Central South University), Changsha 410078, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha 410078, China, and
| | - Guiyuan Li
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China.,National Health Commission Key Laboratory of Carcinogenesis (Central South University), Changsha 410078, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha 410078, China, and
| | - Jianhong Lu
- Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China,
| | - Jian Ma
- From the Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China, .,Cancer Research Institute, Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410078, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Changsha 410013, China.,National Health Commission Key Laboratory of Carcinogenesis (Central South University), Changsha 410078, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha 410078, China, and
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18
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Wang Z, Lv Z, Ding H, Xu Q, Sun L, Jing J, Yuan Y. Role of serum EBV-VCA IgG detection in assessing gastric cancer risk and prognosis in Northern Chinese population. Cancer Med 2018; 7:5760-5774. [PMID: 30306734 PMCID: PMC6246934 DOI: 10.1002/cam4.1792] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 08/09/2018] [Accepted: 08/28/2018] [Indexed: 12/14/2022] Open
Abstract
The study aimed to investigate the role of serum EBV‐VCA IgG in assessing gastric cancer (GC) risk and prognosis. A total of 1790 Northern Chinese participants with pathologically confirmed disease underwent EBV‐VCA IgG serologic testing using enzyme‐linked immunosorbent assay (ELISA), including 821 controls, 410 atrophic gastritis (AG) patients, and 559 GC patients. We found that positive EBV‐VCA IgG was significantly associated with GC and its precursor, conferring a 1.55‐ and 1.36‐fold increased risk of GC and AG, respectively (P = 0.001, 95% CI = 1.21‐1.99; P = 0.011, 95% CI = 1.07‐1.72, respectively). The risk effects were more remarkable in younger, female, and Helicobacter pylori‐negative individuals than in older, male, and H. pylori‐positive individuals. EBV‐VCA IgG‐positive subjects had a lower PGI/II ratio than EBV‐VCA IgG‐negative subjects (median 8.0 vs 8.8, P = 0.001), especially those in the H. pylori‐positive (median 6.1 vs 6.8, P = 0.027) and GC subgroups (median 6.4 vs 7.9, P = 0.020). In the intestinal GC subgroup, the survival of EBV‐VCA IgG‐positive patients was worse than that of EBV‐VCA IgG‐negative patients (P = 0.041, HR = 2.45, 95% CI = 1.04‐5.78). Our study suggests that EBV‐VCA IgG seropositivity has potential in predicting the risk of GC and its precursor as well as the prognosis of histologically classified GC. This is an innovative report about the role of serum EBV‐VCA IgG detection in assessing the risk of gastric cancer (GC) and its precursor as well as GC prognosis. And this is the first report about the relationship between EBV‐VCA IgG serology assay and gastric function status. Our study provides theoretical and experimental basis for evaluating the potential of serum EBV‐VCA IgG as a biomarker in prediction of GC risk and prognosis.
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Affiliation(s)
- Zeyang Wang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China.,Liaoning Provincial Education Department, Key Laboratory of Cancer Etiology and Prevention (China Medical University), Shenyang, China.,Key Laboratory of Pathogen and Prevention of Digestive tract tumor in Liaoning Province, Shenyang, China
| | - Zhi Lv
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China.,Liaoning Provincial Education Department, Key Laboratory of Cancer Etiology and Prevention (China Medical University), Shenyang, China.,Key Laboratory of Pathogen and Prevention of Digestive tract tumor in Liaoning Province, Shenyang, China
| | - Hanxi Ding
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China.,Liaoning Provincial Education Department, Key Laboratory of Cancer Etiology and Prevention (China Medical University), Shenyang, China.,Key Laboratory of Pathogen and Prevention of Digestive tract tumor in Liaoning Province, Shenyang, China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China.,Liaoning Provincial Education Department, Key Laboratory of Cancer Etiology and Prevention (China Medical University), Shenyang, China.,Key Laboratory of Pathogen and Prevention of Digestive tract tumor in Liaoning Province, Shenyang, China
| | - Liping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China.,Liaoning Provincial Education Department, Key Laboratory of Cancer Etiology and Prevention (China Medical University), Shenyang, China.,Key Laboratory of Pathogen and Prevention of Digestive tract tumor in Liaoning Province, Shenyang, China
| | - Jingjing Jing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China.,Liaoning Provincial Education Department, Key Laboratory of Cancer Etiology and Prevention (China Medical University), Shenyang, China.,Key Laboratory of Pathogen and Prevention of Digestive tract tumor in Liaoning Province, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China.,Liaoning Provincial Education Department, Key Laboratory of Cancer Etiology and Prevention (China Medical University), Shenyang, China.,Key Laboratory of Pathogen and Prevention of Digestive tract tumor in Liaoning Province, Shenyang, China
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19
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Varga MG, Cai H, Waterboer T, Murphy G, Shimazu T, Taylor PR, Qiao YL, Park SK, Yoo KY, Jee SH, Cho ER, Kim J, Abnet CC, Tsugane S, Cai Q, Zheng W, Pawlita M, Shu XO, Epplein M. Epstein-Barr Virus Antibody Titers Are Not Associated with Gastric Cancer Risk in East Asia. Dig Dis Sci 2018; 63:2765-2772. [PMID: 29948559 PMCID: PMC6139270 DOI: 10.1007/s10620-018-5154-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 05/30/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND Epstein-Barr virus (EBV)-positive gastric cancers represent a distinct subtype of gastric cancers and account for nearly 10% of the gastric cancer burden, yet risk detection strategies for this cancer subtype are lacking. METHODS We conducted a nested case-control study where we assayed 4 EBV antigens [viral capsid antigen (VCA), early antigen (EA), Epstein-Barr nuclear antigen (EBNA), and BZLF1-encoded replication activator protein (ZEBRA)] in either sera or plasma from 1447 gastric cancer cases and 1797 controls obtained from seven prospective cohorts representing individuals from the high gastric cancer-risk countries of China, Japan, and Korea. RESULTS The prevalence of EBV sero-positivity was universal with the exception of one sero-negative individual, and the highest titers of the EBV antigens VCA (OR 0.95, 95% CI 0.78-1.17), EBNA (OR 0.88, 95% CI 0.72-1.08), EA (OR 0.97, 95% CI 0.79-1.19), and ZEBRA (OR 0.87, 95% CI 0.71-1.07) were not associated with risk of incident gastric cancer. When we stratified these data by H. pylori status, there was no change in the association. CONCLUSIONS Multiplex serology of the aforementioned EBV antigens in serum may not be a suitable biomarker for predicting gastric cancer risk in East Asian populations.
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Affiliation(s)
- Matthew G. Varga
- Department of Epidemiology, Gillings School of Global Public Health
and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel
Hill, 3207B Michael Hooker Research Center, Chapel Hill, NC 27599, USA,Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA
| | - Hui Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA
| | - Tim Waterboer
- Division of Molecular Diagnostics of Oncogenic Infections, Research
Program in Infection, Inflammation, and Cancer, German Cancer Research Center
(DFKZ), 69120 Heidelberg, Germany
| | - Gwen Murphy
- Division of Cancer Epidemiology and Genetics, National Cancer
Institute, Bethesda, MD 20892, USA
| | - Taichi Shimazu
- Epidemiology and Prevention Group, National Cancer Center, Tokyo
104-0045, Japan
| | - Phil R. Taylor
- Division of Cancer Epidemiology and Genetics, National Cancer
Institute, Bethesda, MD 20892, USA
| | - You-Lin Qiao
- Department of Cancer Epidemiology, Chinese Academy of Medical
Sciences and Peking Union Medial College, Beijing 100021, China
| | - Sue K. Park
- Department of Biomedical Sciences, Cancer Research Institute, Seoul
National University College of Medicine, Seoul 110-799, Korea
| | - Keun-Young Yoo
- Department of Preventive Medicine, Seoul National University College
of Medicine, Seoul 110-799, Korea
| | - Sun Ha Jee
- Department of Epidemiology and Health Promotion, Institute for
Health Promotion, Yonsei University, Seoul 120-752, Korea
| | - Eo Rin Cho
- Department of Epidemiology and Health Promotion, Institute for
Health Promotion, Yonsei University, Seoul 120-752, Korea
| | - Jeongseon Kim
- Division of Cancer Epidemiology and Prevention, Research Institute,
National Cancer Center, Goyang 410-769, Korea
| | - Christian C. Abnet
- Division of Cancer Epidemiology and Genetics, National Cancer
Institute, Bethesda, MD 20892, USA
| | - Shoichiro Tsugane
- Epidemiology and Prevention Group, National Cancer Center, Tokyo
104-0045, Japan
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, Research
Program in Infection, Inflammation, and Cancer, German Cancer Research Center
(DFKZ), 69120 Heidelberg, Germany
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA
| | - Meira Epplein
- Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA,Department of Population Health Sciences, Duke University and
Cancer Control and Population Sciences Program, Duke Cancer Institute, Durham, NC
27705, USA
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20
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Pandey S, Jha HC, Shukla SK, Shirley MK, Robertson ES. Epigenetic Regulation of Tumor Suppressors by Helicobacter pylori Enhances EBV-Induced Proliferation of Gastric Epithelial Cells. mBio 2018; 9:e00649-18. [PMID: 29691341 PMCID: PMC5915740 DOI: 10.1128/mbio.00649-18] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 03/27/2018] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori and Epstein-Barr virus (EBV) are two well-known contributors to cancer and can establish lifelong persistent infection in the host. This leads to chronic inflammation, which also contributes to development of cancer. Association with H. pylori increases the risk of gastric carcinoma, and coexistence with EBV enhances proliferation of infected cells. Further, H. pylori-EBV coinfection causes chronic inflammation in pediatric patients. We have established an H. pylori-EBV coinfection model system using human gastric epithelial cells. We showed that H. pylori infection can increase the oncogenic phenotype of EBV-infected cells and that the cytotoxin-associated gene (CagA) protein encoded by H. pylori stimulated EBV-mediated cell proliferation in this coinfection model system. This led to increased expression of DNA methyl transferases (DNMTs), which reprogrammed cellular transcriptional profiles, including those of tumor suppressor genes (TSGs), through hypermethylation. These findings provide new insights into a molecular mechanism whereby cooperativity between two oncogenic agents leads to enhanced oncogenic activity of gastric cancer cells.IMPORTANCE We have studied the cooperativity between H. pylori and EBV, two known oncogenic agents. This led to an enhanced oncogenic phenotype in gastric epithelial cells. We now demonstrate that EBV-driven epigenetic modifications are enhanced in the presence of H. pylori, more specifically, in the presence of its CagA secretory antigen. This results in increased proliferation of the infected gastric cells. Our findings now elucidate a molecular mechanism whereby expression of cellular DNA methyl transferases is induced influencing infection by EBV. Hypermethylation of the regulatory genomic regions of tumor suppressor genes results in their silencing. This drastically affects the expression of cell cycle, apoptosis, and DNA repair genes, which dysregulates their associated processes, and promotion of the oncogenic phenotype.
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Affiliation(s)
- Saurabh Pandey
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hem Chandra Jha
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sanket Kumar Shukla
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Meghan K Shirley
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Erle S Robertson
- Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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21
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Elevated Levels of Interferon- γ Are Associated with High Levels of Epstein-Barr Virus Reactivation in Patients with the Intestinal Type of Gastric Cancer. J Immunol Res 2017; 2017:7069242. [PMID: 29349089 PMCID: PMC5733903 DOI: 10.1155/2017/7069242] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 09/05/2017] [Accepted: 09/14/2017] [Indexed: 12/13/2022] Open
Abstract
Background The inflammatory response directed against Helicobacter pylori (HP) is believed to be one of the main triggers of the appearance of gastric lesions and their progression to gastric cancer (GC). Epstein-Barr virus (EBV) has been found responsible for about 10% of all GCs, but the inflammatory response has not been studied in GC patients with evidence of high levels of EBV reactivation. Objective To determine the relationship between inflammation and antibodies against EBV reactivation antigens, HP, and the bacterium virulence factor CagA in patients with GC. Methods 127 GC patients, 46 gastritis patients, and 197 healthy subjects were studied. IL-1β, IL-6, IL-8, IL-10, TNF-α, TGF-β, MCP-1, and IFN-γ levels were measured in serum or plasma and compared against the antibody titers of VCA-IgG, HP, and the HP virulence factor CagA. Statistical associations were estimated. Results Significant ORs and positive trends were found between VCA-IgG and IFN-γ, specifically for patients with GC of intestinal type (OR: 6.4, 95% C.I. 1.2–35.4) (p < 0.044). Conclusions We confirmed a positive association between a marker of EBV reactivation and intestinal gastric cancer and present evidence of a correlation with elevated serum levels of IFN-γ, but not with the other cytokines.
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22
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Nandakumar A, Uwatoko F, Yamamoto M, Tomita K, Majima HJ, Akiba S, Koriyama C. Radiation-induced Epstein-Barr virus reactivation in gastric cancer cells with latent EBV infection. Tumour Biol 2017; 39:1010428317717718. [PMID: 28675108 DOI: 10.1177/1010428317717718] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Epstein-Barr virus, a ubiquitous human herpes virus with oncogenic activity, can be found in 6%-16% of gastric carcinomas worldwide. In Epstein-Barr virus-associated gastric carcinoma, only a few latent genes of the virus are expressed. Ionizing irradiation was shown to induce lytic Epstein-Barr virus infection in lymphoblastoid cell lines with latent Epstein-Barr virus infection. In this study, we examined the effect of ionizing radiation on the Epstein-Barr virus reactivation in a gastric epithelial cancer cell line (SNU-719, an Epstein-Barr virus-associated gastric carcinoma cell line). Irradiation with X-ray (dose = 5 and 10 Gy; dose rate = 0.5398 Gy/min) killed approximately 25% and 50% of cultured SNU-719 cells, respectively, in 48 h. Ionizing radiation increased the messenger RNA expression of immediate early Epstein-Barr virus lytic genes (BZLF1 and BRLF1), determined by real-time reverse transcription polymerase chain reaction, in a dose-dependent manner at 48 h and, to a slightly lesser extent, at 72 h after irradiation. Similar findings were observed for other Epstein-Barr virus lytic genes (BMRF1, BLLF1, and BcLF1). After radiation, the expression of transforming growth factor beta 1 messenger RNA increased and reached a peak in 12-24 h, and the high-level expression of the Epstein-Barr virus immediate early genes can convert latent Epstein-Barr virus infection into the lytic form and result in the release of infectious Epstein-Barr virus. To conclude, Ionizing radiation activates lytic Epstein-Barr virus gene expression in the SNU-719 cell line mainly through nuclear factor kappaB activation. We made a brief review of literature to explore underlying mechanism involved in transforming growth factor beta-induced Epstein-Barr virus reactivation. A possible involvement of nuclear factor kappaB was hypothesized.
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Affiliation(s)
- Athira Nandakumar
- 1 Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Futoshi Uwatoko
- 1 Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Megumi Yamamoto
- 2 Department of Basic Medical Sciences, National Institute for Minamata Disease, Minamata, Japan
| | - Kazuo Tomita
- 3 Department of Dental Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Hideyuki J Majima
- 3 Department of Dental Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Suminori Akiba
- 1 Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Chihaya Koriyama
- 1 Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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23
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Abstract
Gastric cancer is the fifth most incident and the third most common cause of cancer-related death in the world. Infection with Helicobacter pylori is the major risk factor for this disease. Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in the cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis, and immune surveillance. Comprehensive molecular analyses of gastric cancer have disclosed the complex heterogeneity of this disease. In particular, these analyses have confirmed that Epstein-Barr virus (EBV)-positive gastric cancer is a distinct entity. The identification of gastric cancer subtypes characterized by recognizable molecular profiles may pave the way for a more personalized clinical management and to the identification of novel therapeutic targets and biomarkers for screening, prognosis, prediction of response to treatment, and monitoring of gastric cancer progression.
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24
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朱 晓, 李 夏, 李 素, 于 红. EBV相关性胃癌研究进展. Shijie Huaren Xiaohua Zazhi 2017; 25:1375-1381. [DOI: 10.11569/wcjd.v25.i15.1375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
胃癌细胞中存在Epstein-Barr病毒(Epstein-Barr virus, EBV)者被称为EBV相关性胃癌(Epstein-Barr virus-associated gastric carcinoma, EBVaGC). 近年来EBVaGC作为一种独特的分子亚型疾病逐渐被人们所认知, 全球胃癌患者中平均有10%者为EBVaGC. 本文对EBVaGC近年来在流行病学、临床病理特征、发病机制、治疗及预后等方面的研究进展作一综述. 但目前对EBVaGC的研究尚不明确, 且尚无临床诊疗规范与共识, 也带来了新的挑战和机遇.
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25
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Ribeiro J, Oliveira C, Malta M, Sousa H. Epstein-Barr virus gene expression and latency pattern in gastric carcinomas: a systematic review. Future Oncol 2017; 13:567-579. [PMID: 28118740 DOI: 10.2217/fon-2016-0475] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
METHODS A systematic review of literature was conducted to identify all published reports regarding the expression of Epstein-Barr Virus (EBV) proteins/transcripts and EBV latency patterns in EBV-associated gastric carcinomas (EBVaGC). RESULTS The literature search retrieved 247 papers, of which 25 papers matched the inclusion criteria. The analysis reveals that the most frequently expressed EBV latent proteins are EBNA1 (98.1%) and LMP2A (53.8%), while LMP1 and LMP2B are present in only 10% of cases. Lytic proteins, such as BARF0 and BARF1, and other lytic transcripts are present in almost half of cases. CONCLUSION EBVaGC seems to display a unique transcription/latency pattern that does not fit the 'standard' EBV latency patterns and therefore should be further studied to better understand EBVaGC carcinogenesis.
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Affiliation(s)
- Joana Ribeiro
- Molecular Oncology & Viral Pathology Group (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal.,Virology Service, Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal.,Faculty of Medicine of Porto University (FMUP), Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.,Research Department, Portuguese League Against Cancer (Liga Portuguesa Contra o Cancro - Núcleo Regional do Norte), Estrada Interior da Circunvalação 6657, 4200 Porto, Portugal
| | - Cláudia Oliveira
- Molecular Oncology & Viral Pathology Group (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal.,Abel Salazar Institute for the Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Mariana Malta
- Molecular Oncology & Viral Pathology Group (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal.,Abel Salazar Institute for the Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Hugo Sousa
- Molecular Oncology & Viral Pathology Group (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal.,Virology Service, Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
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26
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Figueiredo C, Camargo MC, Leite M, Fuentes-Pananá EM, Rabkin CS, Machado JC. Pathogenesis of Gastric Cancer: Genetics and Molecular Classification. Curr Top Microbiol Immunol 2017. [PMID: 28124158 DOI: 10.1007/978-3-319-50520-6_12.erratum.in:currtopmicrobiolimmunol.2017;400:e1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
Gastric cancer is the fifth most incident and the third most common cause of cancer-related death in the world. Infection with Helicobacter pylori is the major risk factor for this disease. Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in the cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis, and immune surveillance. Comprehensive molecular analyses of gastric cancer have disclosed the complex heterogeneity of this disease. In particular, these analyses have confirmed that Epstein-Barr virus (EBV)-positive gastric cancer is a distinct entity. The identification of gastric cancer subtypes characterized by recognizable molecular profiles may pave the way for a more personalized clinical management and to the identification of novel therapeutic targets and biomarkers for screening, prognosis, prediction of response to treatment, and monitoring of gastric cancer progression.
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Affiliation(s)
- Ceu Figueiredo
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
| | - M C Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, ML, USA
| | - Marina Leite
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
| | - Ezequiel M Fuentes-Pananá
- Research Unit of Cancer and Virology, Children's Hospital of Mexico "Federico Gomez", Mexico City, Mexico
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, ML, USA
| | - José C Machado
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. .,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal. .,Faculty of Medicine of the University of Porto, Porto, Portugal.
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27
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Camargo MC, Kim KM, Matsuo K, Torres J, Liao LM, Morgan D, Michel A, Waterboer T, Zabaleta J, Dominguez RL, Yatabe Y, Kim S, Rocha-Guevara ER, Lissowska J, Pawlita M, Rabkin CS. Anti-Helicobacter pylori Antibody Profiles in Epstein-Barr virus (EBV)-Positive and EBV-Negative Gastric Cancer. Helicobacter 2016; 21:153-7. [PMID: 26251258 PMCID: PMC5003173 DOI: 10.1111/hel.12249] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Helicobacter pylori is the primary cause of gastric cancer, but about 9% of cases harbor Epstein-Barr virus (EBV) in the tumor cells. There is limited evidence on the possible interaction or antagonism between these infectious agents in gastric carcinogenesis. METHODS We compared H. pylori serologic profiles of EBV-positive (n = 58) and EBV-negative (n = 111) noncardia gastric cancer patients from the United States National Cancer Institute's International EBV-Gastric Cancer Consortium. EBV positivity of tumors was assessed by in situ hybridization. Serum levels of 15 antibodies to immunogenic proteins of H. pylori (Cad, CagA, Cagδ, CagM, Catalase, GroEL, HcpC, HP0231, HP0305, HpaA, HyuA, NapA, Omp, UreA, VacA) were assessed using bead-based multiplex serology. Logistic regression models were used to adjust odds ratios (OR) for country, age, sex, and year of diagnosis. RESULTS Seropositivity to individual proteins ranged up to 90% overall. Antibodies to Catalase were borderline associated with tumor EBV positivity (adjusted OR = 3.15, p = .0024, Bonferroni corrected p = .036). Distributions of other antibodies did not vary by tumor EBV status. CONCLUSION Similarity of host-response indicates the essential etiological role of H. pylori in EBV-positive gastric cancer.
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Affiliation(s)
- M. Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Kyoung-Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keitaro Matsuo
- Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, CMN SXXI, Instituto Mexicano del Seguro Social, México City, México
| | - Linda M. Liao
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Douglas Morgan
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA
| | - Angelika Michel
- Division of Genome Modifications and Carcinogenesis, Infection and Cancer Program, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Tim Waterboer
- Division of Genome Modifications and Carcinogenesis, Infection and Cancer Program, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Jovanny Zabaleta
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Ricardo L. Dominguez
- Department of Medicine, Western Regional Hospital, Santa Rosa de Copan, Honduras
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Erick R. Rocha-Guevara
- Hospital de Oncología, CMN SXXI, Instituto Mexicano del Seguro Social, México City, México
| | - Jolanta Lissowska
- Division of Cancer Epidemiology and Prevention, M Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Michael Pawlita
- Division of Genome Modifications and Carcinogenesis, Infection and Cancer Program, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Charles S. Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
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28
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Cárdenas-Mondragón MG, Torres J, Flores-Luna L, Camorlinga-Ponce M, Carreón-Talavera R, Gomez-Delgado A, Kasamatsu E, Fuentes-Pananá EM. Case–control study of Epstein–Barr virus and Helicobacter pylori serology in Latin American patients with gastric disease. Br J Cancer 2015; 112:1866-73. [PMID: 25996206 PMCID: PMC4580389 DOI: 10.1038/bjc.2015.175] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/21/2015] [Accepted: 04/29/2015] [Indexed: 02/07/2023] Open
Abstract
Background: Chronic tissue damage induced by Helicobacter pylori (HP)-driven inflammation is considered the main risk of gastric carcinoma (GC). Epstein–Barr virus (EBV) infection has also been associated with GC. In this study, we aim to address the role of EBV in inflammatory GC precursor lesions and its added risk to HP infection. Methods: Antibodies against EBV, HP and the bacterial virulence factor CagA were measured in sera from 525 Mexican and Paraguayan patients with gastric disease. Gastric samples were characterised according to the updated Sydney classification and associations were estimated between antibody responses and severity of both tissue damage and inflammation. Results: We found significant associations (odd ratios and trends) between EBV and HP copositivity and premalignant lesions and intestinal-type GC. The EBV and HP coinfection was also significantly associated with increased infiltration of immune cells. No association was found between EBV and the less inflammation-driven diffuse-type GC. Conclusions: Our study suggests that EBV co-participates with HP to induce severe inflammation, increasing the risk of progression to intestinal-type GC.
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Affiliation(s)
- M G Cárdenas-Mondragón
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría, CMN Siglo-XXI, Instituto Mexicano del Seguro Social (IMSS), Avenida Cuauhtémoc 330, Colonia Doctores, Delegación Cuauhtémoc, Ciudad de México, DF, CP 06720, México
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Abstract
Epstein-Barr virus (EBV) infection is found in a subset of gastric cancers. Previous reviews have exclusively focused on EBV-encoded small RNA (EBER) positivity in gastric cancer tissues, but a comprehensive evaluation of other type of studies is lacking.We searched the PubMed database up to September, 2014, and performed a systematic review.We considered studies comparing EBV nucleic acids positivity in gastric cancer tissue with positivity in either adjacent non-tumor tissue of cancer patients or non-tumor mucosa from healthy individuals, patients with benign gastric diseases, or deceased individuals. We also considered studies comparing EBV antibodies in serum from cancer patients and healthy controls.Selection of potentially eligible studies and data extraction were performed by 2 independent reviewers. Due to the heterogeneity of studies, we did not perform formal meta-analysis.Forty-seven studies (8069 cases and 1840 controls) were identified. EBER positivity determined by in situ hybridization (ISH) was significantly higher in cancer tissues (range 5.0%-17.9%) than in adjacent mucosa from the same patients or biopsies from all control groups (almost 0%). High EBV nuclear antigen-1 (EBNA-1) positivity by PCR was found in gastric cancer tissues, but most were not validated by ISH or adjusted for inflammatory severity and lymphocyte infiltration. Only 4 studies tested for EBV antibodies, with large variation in the seropositivities of different antibodies in both cases and controls, and did not find an association between EBV seropositivity and gastric cancer.In summary, tissue-based ISH methods strongly suggest an association between EBV infection and gastric cancer, but PCR method alone is invalid to confirm such association. Very limited evidence from serological studies and the lack of novel antibodies warrant further investigations to identify potential risk factors of EBV for gastric cancer.
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Affiliation(s)
- Xin-Zu Chen
- From the Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany (X-ZC, HC, FAC, HB); Department of Gastrointestinal Surgery (X-ZC, J-KH); Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (X-ZC, J-KH); and German Cancer Consortium (DKTK), Heidelberg, Germany (HB)
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Coghill AE, Hildesheim A. Epstein-Barr virus antibodies and the risk of associated malignancies: review of the literature. Am J Epidemiol 2014; 180:687-95. [PMID: 25167864 DOI: 10.1093/aje/kwu176] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV), a ubiquitous herpes virus that infects 90% of humans by adulthood, is linked to the development of various cancers, including nasopharyngeal carcinoma, gastric cancer, Burkitt lymphoma, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma. We reviewed the literature published since 1980 regarding an association between antibodies against EBV proteins and the risk of EBV-associated malignancies. Immunoglobulin A antibody levels that are elevated before diagnosis have consistently been associated with the risk of nasopharyngeal carcinoma, and patients with Hodgkin lymphoma have significantly higher immunoglobulin G antibody levels than disease-free controls. However, the link between the immune response to EBV and other EBV-associated malignancies was less clear. Although evidence of an association between the risk of Burkitt lymphoma and immunoglobulin G antibodies was consistent for available studies, the sample sizes were limited. Evidence for a link between antibodies against EBV and risk of either gastric cancer or NHL was inconsistent. Future investigations should account for tumor EBV status because only 7%-10% of gastric tumors and select NHL subtypes are related to EBV infection. Comparing differences in the associations between the humoral immune response to EBV and disease risk across cancers may help elucidate how this ubiquitous virus contributes to distinct tumors globally.
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31
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Rickinson AB. Co-infections, inflammation and oncogenesis: future directions for EBV research. Semin Cancer Biol 2014; 26:99-115. [PMID: 24751797 DOI: 10.1016/j.semcancer.2014.04.004] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 04/04/2014] [Indexed: 12/24/2022]
Abstract
Epstein-Barr virus (EBV) is aetiologically linked to a wide range of human tumours. Some arise as accidents of the virus' lifestyle in its natural niche, the B lymphoid system; these include B-lymphoproliferative disease of the immunocompromised, Hodgkin Lymphoma, Burkitt Lymphoma and particular forms of diffuse large B cell lymphoma. Interestingly, HIV infection increases the incidence of each of these B cell malignancies, though by different degrees and for different reasons. Other EBV-associated tumours arise through rare viral entry into unnatural target tissues; these include all cases of nasal T/NK cell lymphoma and of undifferentiated nasopharyngeal carcinoma plus a small but significant subset of gastric carcinomas, a tumour type more generally associated with chronic Helicobacter pylori infection. Understanding EBV's involvement in the pathogenesis of these different malignancies is an important long-term goal. This article focuses on two overlapping, but relatively neglected, areas of research that could contribute to that goal. The first addresses the mechanisms whereby coincident infections with other pathogens increase the risk of EBV-positive malignancies, and takes as its paradigm the actions of holoendemic malaria and HIV infections as co-factors in Burkitt lymphomagenesis. The second widens the argument to include both infectious and non-infectious sources of chronic inflammation in the pathogenesis of EBV-positive tumours such as T/NK cell lymphoma, nasopharyngeal carcinoma and gastric carcinoma.
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Affiliation(s)
- A B Rickinson
- School of Cancer Sciences, University of Birmingham, Birmingham, UK.
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32
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Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev 2014; 23:700-13. [PMID: 24618998 PMCID: PMC4019373 DOI: 10.1158/1055-9965.epi-13-1057] [Citation(s) in RCA: 1287] [Impact Index Per Article: 117.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Less than a century ago, gastric cancer was the most common cancer in the United States and perhaps throughout the world. Despite its worldwide decline in incidence over the past century, gastric cancer remains a major killer across the globe. This article reviews the epidemiology, screening, and prevention of gastric cancer. We first discuss the descriptive epidemiology of gastric cancer, including its incidence, survival, mortality, and trends over time. Next, we characterize the risk factors for gastric cancer, both environmental and genetic. Serologic markers and histological precursor lesions of gastric cancer and early detection of gastric cancer using these markers are reviewed. Finally, we discuss prevention strategies and provide suggestions for further research.
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Affiliation(s)
- Parisa Karimi
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Farhad Islami
- Institute for Transitional Epidemiology, Mount Sinai School of Medicine, New York, NY, United States
- Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sharmila Anandasabapathy
- Division of Gastroenterology, Department of Medicine, Mount Sinai Medical Center, New York, NY, United States
| | - Neal D. Freedman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Farin Kamangar
- Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Public Health Analysis, School of Community Health and Policy, Morgan State University, Baltimore, MD, United States
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Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev 2014. [PMID: 24618998 DOI: 10.1158/1055-9965].] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Less than a century ago, gastric cancer was the most common cancer in the United States and perhaps throughout the world. Despite its worldwide decline in incidence over the past century, gastric cancer remains a major killer across the globe. This article reviews the epidemiology, screening, and prevention of gastric cancer. We first discuss the descriptive epidemiology of gastric cancer, including its incidence, survival, mortality, and trends over time. Next, we characterize the risk factors for gastric cancer, both environmental and genetic. Serologic markers and histological precursor lesions of gastric cancer and early detection of gastric cancer using these markers are reviewed. Finally, we discuss prevention strategies and provide suggestions for further research.
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Affiliation(s)
- Parisa Karimi
- Authors' Affiliations: Johns Hopkins Bloomberg School of Public Health; Department of Public Health Analysis, School of Community Health and Policy, Morgan State University, Baltimore; Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland; Institute for Transitional Epidemiology, Mount Sinai School of Medicine; Division of Gastroenterology, Department of Medicine, Mount Sinai Medical Center, New York, New York; and Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Camargo MC, Koriyama C, Matsuo K, Kim WH, Herrera-Goepfert R, Liao LM, Yu J, Carrasquilla G, Sung JJ, Alvarado-Cabrero I, Lissowska J, Meneses-Gonzalez F, Yatabe Y, Ding T, Hu N, Taylor PR, Morgan DR, Gulley ML, Torres J, Akiba S, Rabkin CS. Case-case comparison of smoking and alcohol risk associations with Epstein-Barr virus-positive gastric cancer. Int J Cancer 2014; 134:948-53. [PMID: 23904115 PMCID: PMC3961829 DOI: 10.1002/ijc.28402] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 07/05/2013] [Accepted: 07/12/2013] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori is the primary cause of gastric cancer. However, monoclonal Epstein-Barr virus (EBV) nucleic acid is also present in up to 10% of these tumors worldwide. EBV prevalence is increased with male sex, nonantral localization and surgically disrupted anatomy. To further examine associations between EBV and gastric cancer, we organized an international consortium of 11 studies with tumor EBV status assessed by in situ hybridization. We pooled individual-level data on 2,648 gastric cancer patients, including 184 (7%) with EBV-positive cancers; all studies had information on cigarette use (64% smokers) and nine had data on alcohol (57% drinkers). We compared patients with EBV-positive and EBV-negative tumors to evaluate smoking and alcohol interactions with EBV status. To account for within-population clustering, multilevel logistic regression models were used to estimate interaction odds ratios (OR) adjusted for distributions of sex (72% male), age (mean 59 years), tumor histology (56% Lauren intestinal-type), anatomic subsite (61% noncardia) and year of diagnosis (1983-2012). In unadjusted analyses, the OR of EBV positivity with smoking was 2.2 [95% confidence interval (CI) 1.6-3.2]. The OR was attenuated to 1.5 (95% CI 1.01-2.3) by adjustment for the possible confounders. There was no significant interaction of EBV status with alcohol drinking (crude OR 1.4; adjusted OR 1.0). Our data indicate the smoking association with gastric cancer is stronger for EBV-positive than EBV-negative tumors. Conversely, the null association with alcohol does not vary by EBV status. Distinct epidemiologic characteristics of EBV-positive cancer further implicate the virus as a cofactor in gastric carcinogenesis.
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Affiliation(s)
- M. Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Chihaya Koriyama
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Keitaro Matsuo
- Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
| | - Woo-Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | | | - Linda M. Liao
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | | | - Jun Yu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Gabriel Carrasquilla
- Centro de Estudios e Investigación en Salud, Fundación Santa Fe de Bogotá, Bogotá, Colombia
| | - Joseph J.Y. Sung
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Isabel Alvarado-Cabrero
- Servicio de Patología, UMAE Oncología, CMN SXXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Jolanta Lissowska
- Division of Cancer Epidemiology and Prevention, M Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Fernando Meneses-Gonzalez
- Programa de Residencia en Epidemiología, Dirección General Adjunta de Epidemiología, Secretaría de Salud, Mexico City, Mexico
| | - Yashushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Ti Ding
- Shanxi Cancer Hospital, Taiyuan, Shanxi, China
| | - Nan Hu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Philip R. Taylor
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Douglas R. Morgan
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA
- Division of Gastroenterology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Margaret L. Gulley
- Department of Pathology and Laboratory Medicine and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, CMN SXXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Suminori Akiba
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Charles S. Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
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35
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Camargo MC, Kim WH, Chiaravalli AM, Kim KM, Corvalan AH, Matsuo K, Yu J, Sung JJY, Herrera-Goepfert R, Meneses-Gonzalez F, Kijima Y, Natsugoe S, Liao LM, Lissowska J, Kim S, Hu N, Gonzalez CA, Yatabe Y, Koriyama C, Hewitt SM, Akiba S, Gulley ML, Taylor PR, Rabkin CS. Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut 2014; 63:236-43. [PMID: 23580779 PMCID: PMC4384434 DOI: 10.1136/gutjnl-2013-304531] [Citation(s) in RCA: 280] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE About 9% of gastric carcinomas have Epstein-Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors. METHODS We combined individual-level data on 4599 gastric cancer patients diagnosed between 1976 and 2010 from 13 studies in Asia (n=8), Europe (n=3), and Latin America (n=2). EBV positivity of tumours was assessed by in situ hybridisation. Mortality HRs for EBV positivity were estimated by Cox regression models stratified by study, adjusted for distributions of sex (71% male), age (mean 58 years), stage (52% tumour-node-metastasis stages III or IV), tumour histology (49% poorly differentiated, 57% Lauren intestinal-type), anatomic subsite (70% non-cardia) and year of diagnosis. Variations by study and continent were assessed using study-specific HRs for EBV positivity. RESULTS During median 3.0 years follow-up, 49% of patients died. Stage was strongly predictive of mortality, with unadjusted HRs (vs stage I) of 3.1 for stage II, 8.1 for stage III and 13.2 for stage IV. Tumour EBV positivity was 8.2% overall and inversely associated with stage (adjusted OR: 0.79 per unit change). Adjusted for stage and other confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI 0.61 to 0.86), with low heterogeneity among the study populations (p=0.2). The association did not significantly vary across patient or tumour characteristics. There was no significant variation among the three continent-specific HRs (p=0.4). CONCLUSIONS Our findings suggest that tumour EBV positivity is an additional prognostic indicator in gastric cancer. Further studies are warranted to identify the mechanisms underlying this protective association.
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Affiliation(s)
- M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Woo-Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | | | - Kyoung-Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Alejandro H Corvalan
- Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Keitaro Matsuo
- Division of Molecular Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Jun Yu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Joseph J Y Sung
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | | | - Fernando Meneses-Gonzalez
- Programa de Residencia en Epidemiología, Dirección General Adjunta de Epidemiología, Secretaría de Salud, México City, México
| | - Yuko Kijima
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Shoji Natsugoe
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Linda M Liao
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Jolanta Lissowska
- Division of Cancer Epidemiology and Prevention, M Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Sung Kim
- Division of Cancer Epidemiology and Prevention, M Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Nan Hu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Carlos A Gonzalez
- Unit of Nutrition, Environment and Cancer, Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain; on behalf of the Euro-gast EPIC study
| | - Yashushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Chihaya Koriyama
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Stephen M Hewitt
- Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
| | - Suminori Akiba
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine, The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Philip R Taylor
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
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Ikeda T, Kobayashi R, Kogashiwa Y, Matsuda T, Kohno N. Epstein-barr virus diversity in immunocompetent healthy persons: Reassessment of the distribution of genetic variants. J Med Virol 2013; 86:301-5. [DOI: 10.1002/jmv.23715] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2013] [Indexed: 11/06/2022]
Affiliation(s)
- Tetsuya Ikeda
- Department of Oto-Rhino-Laryngology, Oral Surgery; Kyorin University School of Medicine; Tokyo Japan
| | - Ryo Kobayashi
- Department of Microbiology; Tokyo Medical University School of Medicine; Tokyo Japan
| | - Yasunao Kogashiwa
- Department of Oto-Rhino-Laryngology, Oral Surgery; Kyorin University School of Medicine; Tokyo Japan
| | - Takehiro Matsuda
- Department of Oto-Rhino-Laryngology, Oral Surgery; Kyorin University School of Medicine; Tokyo Japan
| | - Naoyuki Kohno
- Department of Oto-Rhino-Laryngology, Oral Surgery; Kyorin University School of Medicine; Tokyo Japan
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Bilici M, Cayir K, Tekin SB, Gundogdu C, Albayrak A, Suleyman B, Ozogul B, Erdemci B, Suleyman H. Effect of mirtazapine on MNNG-induced gastric adenocarcinoma in rats. Asian Pac J Cancer Prev 2013; 13:4897-900. [PMID: 23244077 DOI: 10.7314/apjcp.2012.13.10.4897] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE In this study, anticancer effects of mirtazapine on rats were investigated in an adenocarcinoma model induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and compared with those of cisplatin. MATERIALS AND METHODS For this purpose, 10 mg/kg doses of mirtazapine were administered orally to one group of rats, while 1 mg/kg doses of cisplatin were administered intraperitoneally to another group. At 1 hour after administration, 200 mg/kg doses of MNNG were given orally to both groups. MNNG administration was repeated once every 10 days through 3 months, after which period, gastric tissue was taken and pathologically evaluated. RESULTS Mirtazapine prevented adenocarcinoma induction by MNNG in rats to a greater extent than cisplatin. Some of the rats receiving cisplatin demonstrated severe dysplasia in gastric samples and others exhibited mild dysplasia. Rats given mirtazapine were not observed to suffer severe dysplasia, only mild dysplasia being observed. CONCLUSION For adenocarcinoma induced by MNNG on rats, mirtazapine was determined more effective than cisplatin. In order to make statement about mechanism of anticancer activity of mirtazapine, wider studies are required.
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Affiliation(s)
- Mehmet Bilici
- Ataturk University, Faculty of Medicine, Erzurum, Turkey.
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38
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Bonequi P, Meneses-González F, Correa P, Rabkin CS, Camargo MC. Risk factors for gastric cancer in Latin America: a meta-analysis. Cancer Causes Control 2013; 24:217-31. [PMID: 23224270 PMCID: PMC3961831 DOI: 10.1007/s10552-012-0110-z] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2012] [Accepted: 11/15/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Latin America has among the highest gastric cancer incidence rates in the world, for reasons that are still unknown. In order to identify region-specific risk factors for gastric cancer, we conducted a meta-analysis summarizing published literature. METHODS Searches of PubMed and regional databases for relevant studies published up to December 2011 yielded a total of 29 independent case-control studies. We calculated summary odds ratios (OR) for risk factors reported in at least five studies, including socioeconomic status (education), lifestyle habits (smoking and alcohol use), dietary factors (consumption of fruits, total vegetables, green vegetables, chili pepper, total meat, processed meat, red meat, fish, and salt), and host genetic variants (IL1B-511T, IL1B-31C, IL1RN*2, TNFA-308A, TP53 codon 72 Arg, and GSTM1 null). Study-specific ORs were extracted and summarized using random-effects models. RESULTS Chili pepper was the only region-specific factor reported in at least five studies. Consistent with multifactorial pathogenesis, smoking, alcohol use, high consumption of red meat or processed meat, excessive salt intake, and carriage of IL1RN*2 were each associated with a moderate increase in gastric cancer risk. Conversely, higher levels of education, fruit consumption, and total vegetable consumption were each associated with a moderately decreased risk. The other exposures were not significantly associated. No prospective study data were identified. CONCLUSION Risk factor associations for gastric cancer in Latin America are based on case-control comparisons that have uncertain reliability, particularly with regard to diet; the specific factors identified and their magnitudes of association are largely similar to those globally recognized. Future studies should emphasize prospective data collection and focus on region-specific exposures that may explain high gastric cancer risk.
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Affiliation(s)
- Patricia Bonequi
- Programa de Residencia en Epidemiología, Dirección General Adjunta de Epidemiología, Secretaría de Salud, Mexico City, Mexico
| | - Fernando Meneses-González
- Programa de Residencia en Epidemiología, Dirección General Adjunta de Epidemiología, Secretaría de Salud, Mexico City, Mexico
| | - Pelayo Correa
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Charles S. Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - M. Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
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Treatment of Epstein-Barr virus-associated gastric carcinoma with endoscopic submucosal dissection. Gastrointest Endosc 2012; 76:913-5. [PMID: 22196795 DOI: 10.1016/j.gie.2011.09.040] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Accepted: 09/20/2011] [Indexed: 12/27/2022]
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40
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Ryan JL, Shen YJ, Morgan DR, Thorne LB, Kenney SC, Dominguez RL, Gulley ML. Epstein-Barr virus infection is common in inflamed gastrointestinal mucosa. Dig Dis Sci 2012; 57:1887-98. [PMID: 22410851 PMCID: PMC3535492 DOI: 10.1007/s10620-012-2116-5] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 02/22/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Epstein-Barr virus (EBV) is present in the malignant epithelial cells of 10% of all gastric adenocarcinomas; however, localization of the virus in normal gastrointestinal mucosa is largely unexplored. In the present study, we measured EBV DNA and localized viral gene products in gastritis specimens (n = 89), normal gastric and colonic mucosa (n = 14), Crohn's disease (n = 9), and ulcerative colitis (n = 11) tissues. METHODS A battery of sensitive and specific quantitative polymerase chain reactions targeted six disparate regions of the EBV genome: BamH1 W, EBNA1, LMP1, LMP2, BZLF1, and EBER1. EBV infection was localized by EBV-encoded RNA (EBER) in situ hybridization and by immunohistochemical stains for viral latent proteins LMP1 and LMP2 and for viral lytic proteins BMRF1 and BZLF1. B lymphocytes were identified using CD20 immunostains. RESULTS EBV DNA was essentially undetectable in normal gastric mucosa but was present in 46% of gastritis lesions, 44% of normal colonic mucosa, 55% of Crohn's disease, and 64% of ulcerative colitis samples. Levels of EBV DNA exceeded what would be expected based on the numbers of B lymphocytes in inflamed tissues, suggesting that EBV is preferentially localized to inflammatory gastrointestinal lesions. Histochemical staining revealed EBER expression in lymphoid cells of some PCR-positive lesions. The viral lytic viral proteins, BMRF1 and BZLF1, were expressed in lymphoid cells of two ulcerative colitis tissues, both of which had relatively high viral loads by quantitative PCR. CONCLUSION EBV-infected lymphocytes are frequently present in inflamed gastric and colonic mucosa. Active viral replication in some lesions raises the possibility of virus-related perpetuation of gastrointestinal inflammation.
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Affiliation(s)
- Julie L. Ryan
- Department of Dermatology & Radiation Oncology, University of Rochester Medical Center, Rochester, NY
| | - You-Jun Shen
- Virginia Beach General Hospital, Virginia Beach, VA
| | - Douglas R. Morgan
- Gastroenterology and Hepatology Division, Department of Medicine, University of North Carolina, Chapel Hill, NC
| | - Leigh B. Thorne
- Department of Pathology and Laboratory Medicine and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
| | - Shannon C. Kenney
- Departments of Medicine and Oncology, University of Wisconsin, Madison, WI
| | - Ricardo L. Dominguez
- Department of Gastroenterology, Western Regional Hospital, Santa Rosa de Copan, Honduras
| | - Margaret L. Gulley
- Department of Pathology and Laboratory Medicine and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
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Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a recently recognized entity, which is defined by the presence of EBV in the gastric carcinoma cells. EBVaGC represents about 10% of gastric carcinoma worldwide, and >80,000 patients are estimated to develop EBVaGC annually. EBVaGC shows some distinct clinicopathologic characteristics, such as male predominance, predisposition to the proximal stomach, and a high proportion in diffuse-type gastric carcinomas. Besides, EBVaGC also shows characteristic molecular abnormality, that is, global and nonrandom CpG-island methylation of the promoter region of many cancer-related genes, which causes downregulation of their expression. Moreover, EBVaGC has a relative favorable prognosis. The uniform presence of EBV-encoded small RNA in tumor cells but not in the surrounding normal epithelial cells, and the detection of monoclonal EBV episomes in EBVaGC, strongly suggests that EBV play an etiological role in gastric carcinogenesis. Therefore, EBVaGC should be regarded as a distinct entity of gastric carcinoma, although it only accounts for a relatively small fraction of total gastric carcinomas. In this review, the epidemiological and clinicopathologic features of EBVaGC and the genetic abnormalities of EBVaGC cell including chromosomal and epigenetic abnormalities are described. The roles of EBV in gastric carcinogenesis are discussed. We make an emphasis on the EBV latency pattern and genome polymorphisms as well as local immunity in EBVaGC. In addition, the treatment of EBVaGC is also briefly discussed. Taken together, this review aims to give the reader a full understanding of a newly defined entity of gastric carcinoma, EBVaGC.
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Tsai PJ. Spatial autocorrelation calculations of the nine malignant neoplasms in Taiwan in 2005-2009: a gender comparison study. CHINESE JOURNAL OF CANCER 2011; 30:757-65. [PMID: 22035856 PMCID: PMC4013298 DOI: 10.5732/cjc.011.10122] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Spatial analytical techniques and models are often used in epidemiology to identify spatial anomalies (hotspots) in disease regions. These analytical approaches can be used to identify not only the location of such hotspots, but also their spatial patterns. We used spatial autocorrelation methodologies, including Global Moran's I and Local Getis-Ord statistics, to describe and map spatial clusters and areas in which nine malignant neoplasms are situated in Taiwan. In addition, we used a logistic regression model to test the characteristics of similarity and dissimilarity between males and females and to formulate the common spatial risk. The mean found by local spatial autocorrelation analysis was used to identify spatial cluster patterns. We found a significant relationship between the leading malignant neoplasms and well-documented spatial risk factors. For instance, in Taiwan, the geographic distribution of clusters where oral cavity cancer in males is prevalent was closely correspond to the locations in central Taiwan with serious metal pollution. In females, clusters of oral cavity cancer were closely related with aboriginal townships in eastern Taiwan, where cigarette smoking, alcohol drinking, and betel nut chewing are commonplace. The difference between males and females in the spatial distributions was stark. Furthermore, areas with a high morbidity of gastric cancer were clustered in aboriginal townships where the occurrence of Helicobacter pylori is frequent. Our results revealed a similarity between both males and females in spatial pattern. Cluster mapping clarified the spatial aspects of both internal and external correlations for the nine malignant neoplasms. In addition, using a method of logistic regression also enabled us to find differentiation between gender-specific spatial patterns.
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Affiliation(s)
- Pui-Jen Tsai
- Center for General Education, Aletheia University, New Taipei 25103, Taiwan.
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Camargo MC, Murphy G, Koriyama C, Pfeiffer RM, Kim WH, Herrera-Goepfert R, Corvalan AH, Carrascal E, Abdirad A, Anwar M, Hao Z, Kattoor J, Yoshiwara-Wakabayashi E, Eizuru Y, Rabkin CS, Akiba S. Determinants of Epstein-Barr virus-positive gastric cancer: an international pooled analysis. Br J Cancer 2011; 105:38-43. [PMID: 21654677 PMCID: PMC3137422 DOI: 10.1038/bjc.2011.215] [Citation(s) in RCA: 131] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 05/10/2011] [Accepted: 05/15/2011] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Meta-analyses of the published literature indicate that about 9% of gastric cancers contain Epstein-Barr virus (EBV), with consistent and significant differences by sex and anatomic subsite. This study aimed to identify additional determinants of EBV positivity and their joint effects. METHODS From 15 international populations with consistent laboratory testing for EBV, we pooled individual-level data for 5081 gastric cancer cases including information on age, sex, subsite, histologic type, diagnostic stage, geographic region, and period of diagnosis. First, we combined population-specific EBV prevalence estimates using random effects meta-analysis. We then aggregated individual-level data to estimate odds ratios of EBV positivity in relation to all variables, accounting for within-population clustering. RESULTS In unadjusted analyses, EBV positivity was significantly higher in males, young subjects, non-antral subsites, diffuse-type histology, and in studies from the Americas. Multivariable analyses confirmed significant associations with histology and region. Sex interacted with age (P=0.003) and subsite (P=0.002) such that male predominance decreased with age for both subsites. The positivity of EBV was not significantly associated with either stage or time period. CONCLUSION Aggregating individual-level data provides additional information over meta-analyses. Distinguishing histologic and geographic features as well as interactions among age, sex, and subsite further support classification of EBV-associated gastric cancer as a distinct aetiologic entity.
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Affiliation(s)
- M C Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard., Rockville, MD 20852, USA.
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Epithelial cell retention of transcriptionally active, P3HR-1-derived heterogeneous Epstein-Barr virus DNA with concurrent loss of parental virus. J Virol 2011; 85:7634-43. [PMID: 21593154 DOI: 10.1128/jvi.00045-11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Deleted, rearranged, heterogeneous (het) Epstein-Barr virus (EBV) DNA with the distinctive capability of disrupting EBV latency has been reported in biopsy samples of EBV-associated tumors whose onset in immunocompetent hosts is characteristically preceded by an antibody response indicative of EBV reactivation. Using the EBV P3HR-1 strain, we have reproduced in long-term culture of SVK epithelial cells an unusual pattern of infection previously observed in a subset of tumor biopsy samples: the persistence of het DNA in the absence of the parental helper virus. Fluorescence in situ hybridization (FISH) of infected cell subclones indicated the retention of het DNA in an integrated form. Incorporation of an intact het DNA molecule was confirmed by PCR, using primers that framed junctions of the four rearranged EBV DNA segments comprising P3HR-1-derived het DNA. Structural analysis of EBV terminal repeats revealed a banding pattern consistent with the integration of het DNA as a concatemer. Linkage of concatemeric monomers was defined at a nucleotide level, and that junctional sequence was detected in cell-free P3HR-1 virion DNA, confirming that subgenomic het DNA was packaged into infectious particles in a concatemeric configuration. Stable integration into cells having lost the standard viral genome allowed the unambiguous designation of het DNA as the source for viral gene products potentially encoded by both. Continuous expression of the latency-to-lytic switch protein Zta and detection of the BALF4 gene product gB, known to expand the target cell range of standard virus when incorporated at augmented levels into infectious progeny, add to a presumption of het DNA-enhanced pathogenesis in diseases of EBV reactivation.
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Boysen T, Friborg J, Stribolt K, Hamilton-Dutoit S, Goertz S, Wohlfahrt J, Melbye M. Epstein-Barr virus-associated gastric carcinoma among patients with pernicious anemia. Int J Cancer 2011; 129:2756-60. [PMID: 21225628 DOI: 10.1002/ijc.25925] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Accepted: 12/10/2010] [Indexed: 12/13/2022]
Abstract
Approximately 9% of gastric carcinomas worldwide are associated with Epstein-Barr virus (EBV), making it the most frequent EBV-associated malignancy. Pernicious anemia, a condition with chronic gastritis and achlorhydria, is strongly associated with gastric carcinoma. Both chronic inflammation and the lack of stomach acid may influence the likelihood of EBV infection of the neoplastic gastric epithelium, but the prevalence of EBV-associated gastric carcinoma among patients with pernicious anemia is unknown. Therefore, we conducted a Danish nationwide case-control study comparing gastric carcinoma patients with pernicious anemia (PA-GC) with those without pernicious anemia (nonPA-GC), frequency matched 1:2. Tumor tissues were reclassified by expert histopathologists blinded to pernicious anemia and EBV status. In total, 186 samples (55 PA-GC and 131 nonPA-GC) were identified. EBV-associated gastric carcinoma (EBV-GC) was more common among PA-GC compared with nonPA-GC, adjusted odds ratio (OR) = 2.53 (CI: 0.88; 7.14), p = 0.08, with further adjustment for lymphocytic infiltrate OR = 2.94 (0.99-8.67), p = 0.05. Gastric carcinomas with signet-ring cell morphology were significantly less common in patients with PA-GC compared with nonPA-GC (OR = 0.05, CI 0.01; 0.24). Although these conditions are rare, we found suggestive evidence that EBV-associated gastric carcinomas are more common among gastric carcinoma patients with pernicious anemia compared with those without.
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Affiliation(s)
- Trine Boysen
- Department of Epidemiology Research,Statens Serum Institut,Copenhagen, Denmark.
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46
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Niller HH, Wolf H, Minarovits J. Viral hit and run-oncogenesis: genetic and epigenetic scenarios. Cancer Lett 2010; 305:200-17. [PMID: 20813452 DOI: 10.1016/j.canlet.2010.08.007] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2010] [Revised: 07/29/2010] [Accepted: 08/09/2010] [Indexed: 12/31/2022]
Abstract
It is well documented that viral genomes either inserted into the cellular DNA or co-replicating with it in episomal form can be lost from neoplastic cells. Therefore, "hit and run"-mechanisms have been a topic of longstanding interest in tumor virology. The basic idea is that the transient acquisition of a complete or incomplete viral genome may be sufficient to induce malignant conversion of host cells in vivo, resulting in neoplastic development. After eliciting a heritable change in the gene expression pattern of the host cell (initiation), the genomes of tumor viruses may be completely lost, i.e. in a hit and run-scenario they are not necessary for the maintenance of the malignant state. The expression of viral oncoproteins and RNAs may interfere not only with regulators of cell proliferation, but also with DNA repair mechanisms. DNA recombinogenic activities induced by tumor viruses or activated by other mechanisms may contribute to the secondary loss of viral genomes from neoplastic cells. Viral oncoproteins can also cause epigenetic dysregulation, thereby reprogramming cellular gene expression in a heritable manner. Thus, we expect that epigenetic scenarios of viral hit and run-tumorigenesis may facilitate new, innovative experiments and clinical studies in spite of the fact that the regular presence of a suspected human tumor virus in an early phase of neoplastic development and its subsequent regular loss have not been demonstrated yet. We propose that virus-specific "epigenetic signatures", i.e. alterations of the host cell epigenome, especially altered DNA methylation patterns, may help to identify viral hit and run-oncogenic events, even after the complete loss of tumor viruses from neoplastic cells.
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Affiliation(s)
- Hans Helmut Niller
- Institute for Medical Microbiology and Hygiene of the University of Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, Germany.
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Epidemiological aspects of gastric adenocarcinoma: are predictive diagnostics and targeted preventive measures possible? EPMA J 2010. [PMID: 23199088 PMCID: PMC3405336 DOI: 10.1007/s13167-010-0043-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The incidence of gastric cancer has witnessed major changes over the past decades. Until recently, gastric cancer was a common malignancy in most countries. A striking decline in incidence in most Western populations has occurred since the 1970s, and elucidating the detailed causes for this trend can potentially be of great value for targeted preventive measures. Furthermore, it can add to the understanding of malignant disease and prevention in general. Moreover, the absolute number of cases worldwide is predicted to increase during many years to come. Gastric cancer is typically diagnosed at an advanced stage in symptomatic patients, and there are often no effective curative or palliative or therapeutic options. This fact highlights the need for research aiming to increase our understanding of the etiology of this cancer, facilitating the design of successful targeted preventive strategies for different populations. The future outlook in terms of decreasing gastric cancer deaths would be to identify such intelligent diagnostic tools. In this article, we present a summary of the epidemiology of gastric cancer, with special focus on its etiology.
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48
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Epstein-Barr virus antibody level and gastric cancer risk in Korea: a nested case-control study. Br J Cancer 2009; 101:526-9. [PMID: 19550421 PMCID: PMC2720236 DOI: 10.1038/sj.bjc.6605146] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background: Few cohort studies have investigated Epstein–Barr virus (EBV) infection before the occurrence of gastric cancer. Methods: Among 14 440 cohort participants, 100 incident gastric cancer cases were individually matched to two controls. Epstein–Barr virus antibodies IgG and IgA against viral capsid antigen (VCA), EBV nuclear antigen (EBNA) antibody IgG, and early antigen (EA) antibody IgG were measured using enzyme immunoassays (EIAs). Results: The highest titres of VCA IgG (odds ratio (OR): 1.37, 95% confidence interval (CI): 0.62–3.06) or EBNA IgG (OR: 0.87, 95% CI: 0.51–1.46) were not associated with gastric cancer risk. Conclusion: Higher levels of VCA IgG or EBNA IgG were not associated with increased risk of gastric adenocarcinoma in Koreans.
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49
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Points of recombination in Epstein-Barr virus (EBV) strain P3HR-1-derived heterogeneous DNA as indexes to EBV DNA recombinogenic events in vivo. J Virol 2008; 82:11516-25. [PMID: 18818321 DOI: 10.1128/jvi.01036-08] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Deletions and rearrangements in the genome of Epstein-Barr virus (EBV) strain P3HR-1 generate subgenomic infectious particles that, unlike defective interfering particles in other viral systems, enhance rather than restrict EBV replication in vitro. Reports of comparable heterogeneous (het) DNA in EBV-linked human diseases, based on detection of an abnormal juxtaposition of EBV DNA fragments BamHI W and BamHI Z that disrupts viral latency, prompted us to determine at the nucleotide level all remaining recombination joints formed by the four constituent segments of P3HR-1-derived het DNA. Guided by endonuclease restriction maps, we chose PCR primer pairs that approximated and framed junctions creating the unique BamHI M/B1 and E/S fusion fragments. Sequencing of PCR products revealed points of recombination that lacked regions of extensive homology between constituent fragments. Identical recombination junctions were detected by PCR in EBV-positive salivary samples from human immunodeficiency virus-infected donors, although the W/Z rearrangement that induces EBV reactivation was frequently found in the absence of the other two. In vitro infection of lymphoid cells similarly indicated that not all three het DNA rearrangements need to reside on a composite molecule. These results connote a precision in the recombination process that dictates both composition and regulation of gene segments altered by genomic rearrangement. Moreover, the apparent frequency of het DNA at sites of EBV replication in vivo is consistent with a likely contribution to the pathogenesis of EBV reactivation.
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Saxena A, Nath Prasad K, Chand Ghoshal U, Krishnani N, Roshan Bhagat M, Husain N. Association of Helicobacter pylori and Epstein-Barr virus with gastric cancer and peptic ulcer disease. Scand J Gastroenterol 2008; 43:669-74. [PMID: 18569983 DOI: 10.1080/00365520801909660] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Helicobacter pylori and Epstein-Barr virus (EBV) infections are common world-wide. Though H. pylori infection is a major factor in gastroduodenal diseases, its role in association with EBV infection is unknown. We prospectively studied the association of H. pylori and EBV in patients with gastric cancer (GC) and peptic ulcer disease (PUD). MATERIAL AND METHODS A total of 348 adult patients (non-ulcer dyspepsia (NUD) 241, PUD 45, GC 62) undergoing upper gastrointestinal endoscopy between September 2003 and May 2007 were enrolled in the study. H. pylori infection was diagnosed by rapid urease test, culture, histopathology and polymerase chain reaction (PCR). EBV DNA was detected by non-polymorphic Epstein-Barr nuclear antigen-1 (EBNA-1) gene-based PCR and sequence analysis. RESULTS The rate of H. pylori infection was higher in patients with PUD than in those with GC (80% versus 56.5%, p=0.01) and NUD (80% versus 55.2%, p=0.002). In patients with GC and PUD, EBV DNA was detected more often than in those with NUD (GC versus NUD - 82.3% versus 37.3%, p<0.001; PUD versus NUD - 75.5% versus 37.3%, p<0.001). H. pylori infection and EBV DNA detected in different groups of patients was as follows: 62.2% in PUD, 46.8% in GC and 29.5% in NUD. PUD and GC were significantly associated (p<0.001 and <0.05, respectively) with the presence of H. pylori infection and EBV DNA as compared with NUD. CONCLUSIONS EBV DNA either alone or in combination with H. pylori infection was significantly associated with GC and PUD, suggesting that EBV might play an important role in gastroduodenal pathology.
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Affiliation(s)
- Ashish Saxena
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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