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Iizasa H, Kartika AV, Fekadu S, Okada S, Onomura D, Wadi AFAA, Khatun MM, Moe TM, Nishikawa J, Yoshiyama H. Development of Epstein-Barr virus-associated gastric cancer: Infection, inflammation, and oncogenesis. World J Gastroenterol 2022; 28:6249-6257. [PMID: 36504553 PMCID: PMC9730441 DOI: 10.3748/wjg.v28.i44.6249] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/24/2022] [Accepted: 11/09/2022] [Indexed: 11/25/2022] Open
Abstract
Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) cells originate from a single-cell clone infected with EBV. However, more than 95% of patients with gastric cancer have a history of Helicobacter pylori (H. pylori) infection, and H. pylori is a major causative agent of gastric cancer. Therefore, it has long been argued that H. pylori infection may affect the development of EBVaGC, a subtype of gastric cancer. Atrophic gastrointestinal inflammation, a symptom of H. pylori infection, is observed in the gastric mucosa of EBVaGC. Therefore, it remains unclear whether H. pylori infection is a cofactor for gastric carcinogenesis caused by EBV infection or whether H. pylori and EBV infections act independently on gastric cancer formation. It has been reported that EBV infection assists in the onco-genesis of gastric cancer caused by H. pylori infection. In contrast, several studies have reported that H. pylori infection accelerates tumorigenesis initiated by EBV infection. By reviewing both clinical epidemiological and experimental data, we reorganized the role of H. pylori and EBV infections in gastric cancer formation.
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Affiliation(s)
- Hisashi Iizasa
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| | - Andy Visi Kartika
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
- Faculty of Medicine, Muslim University of Indonesia, Makassar 90231, Indonesia
| | - Sintayehu Fekadu
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
- Department of Medical Microbiology and Parasitology, Hawassa University, College of Medicine and Health Science, Hawassa 1560, Ethiopia
| | - Shunpei Okada
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| | - Daichi Onomura
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| | | | - Mosammat Mahmuda Khatun
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| | - Thin Myat Moe
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
| | - Jun Nishikawa
- Faculty of Laboratory Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
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Suzuki Y, Ito S, Nomura K, Matsui A, Kikuchi D, Hoteya S. Multiple Epstein-Barr virus-associated Gastric Cancers Arising in a Patient with Autoimmune Gastritis. Intern Med 2022; 62:1459-1466. [PMID: 36171131 DOI: 10.2169/internalmedicine.0673-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Epstein-Barr virus-associated gastric cancer (EBVaGC) has been reported to be associated with chronic inflammation of the gastric epithelium caused by Helicobacter pylori infection. Autoimmune gastritis (AIG) is also believed to increase the risk of carcinogenesis. We herein report a case of multiple EBVaGCs that arose in a patient with AIG, highlighting the potential for multiplicity of this entity. In this case, a total of four metachronous EBVaGCs were found after initial Endoscopic submucosal dissection for EBVaGC, all of which were treated endoscopically. This case demonstrates that patients with AIG should be monitored closely for development of EBVaGC.
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Affiliation(s)
- Yugo Suzuki
- Department of Gastroenterology, Toranomon Hospital, Japan
| | - Shinji Ito
- Department of Pathology, Toranomon Hospital, Japan
| | - Kosuke Nomura
- Department of Gastroenterology, Toranomon Hospital, Japan
| | - Akira Matsui
- Department of Gastroenterology, Toranomon Hospital, Japan
| | | | - Shu Hoteya
- Department of Gastroenterology, Toranomon Hospital, Japan
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3
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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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Co-infection relationship with Epstein-Barr virus in gastroduodenal diseases with Helicobacter Pylori. Quantitative PCR and EBNA-1 gene-based approach. Acta Gastroenterol Belg 2022; 85:301-308. [DOI: 10.51821/85.2.9440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Objective: Helicobacter pylori (Hp) and Epstein-Barr virus (EBV) are involved in gastric cancer (GC) etiology. EBV/Hp co- infection was thought synergistically increase gastroduodenal disease occurence. We aimed to determine the presence of EBV/Hp co-infection in gastroduodenal diseases.
Methods: The study group had 68 Hp (+) cases [25 GC, 13 IM (intestinal metaplasia), 30 PU (peptic ulcer)], and the control group had 40 NUD (non-ulcer dyspepsia) cases [20 Hp+, 20 Hp-]. EBV-DNA was detected by non-polymorphic EBNA-1 gene-based qPCR. EBV/EBNA-1 IgG levels were determined by quantitative and qualitative ELISA methods, respectively.
Results: EBV-DNA positivity was 32% (8/25), 6.6% (2/30) and 5% (1/20) in GC, PU and NUD Hp (+) cases, respectively. There was a significant difference (p = 0.001) between GC (32%) and NUD Hp (+) (5%) cases in terms of EBV-DNA positivity. Mean EBV-DNA copy numbers were 6568.54 ± 20351, 30.60 ± 159.88 and 13.85 ± 61.93 for GC, PU, and NUD, respectively. In terms of the mean EBV-DNA copy number, a significant difference was found between the groups (p = 0.005). In terms of EBV/EBNA-1 IgG antibody positivity, no significant difference was found between GC and NUD cases (p = 0.248). EBV DNA positivity was found to be significant (odds ration [OR] = 26.71 (p=0.009, %95CI 2.286- 312.041) in multivariate logistic regression.
Conclusioin: Although we had a small number of GC cases, it can be suggested that the estimated risk created by the synergistic effect based on the addition of EBV increased 26 times in the presence of Hp in GC.
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Manuel Lopes de Sousa H, Patrícia Costa Ribeiro J, Basílio Timóteo M. Epstein-Barr Virus-Associated Gastric Cancer: Old Entity with New Relevance. Infect Dis (Lond) 2021. [DOI: 10.5772/intechopen.93649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Gastric cancer (GC) represents a major public health issue worldwide, being the fifth most common cancer and one of the leading causes of death by cancer. In 2014, The Cancer Genome Atlas (TCGA) established that tumors positive for Epstein-Barr virus (EBV) are considered a specific subtype of GC (EBVaGC). Several meta-analyses have shown that EBVaGC represents almost 10% of all gastric cancer worldwide, with small differences in the geographic distribution. This tumor subtype has a high potential of being clinically relevant and studies have shown that it has specific features, a better prognosis, and increased overall survival. In this review, we summarize some of the most frequent aspects of EBVaGC, including the specific features of this GC subtype, data regarding the potential steps of EBVaGC carcinogenesis, and perspectives on treatment opportunities.
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Epstein-Barr virus associated gastric dysplasia: a new rare entity? Virchows Arch 2021; 480:939-944. [PMID: 34537878 DOI: 10.1007/s00428-021-03206-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/22/2022]
Abstract
Epstein-Barr virus (EBV) infection characterizes a portion of gastric adenocarcinomas. However, since there is lack of evidence of EBV presence in pre-neoplastic lesions of gastric mucosa, the etiologic role of EBV in gastric carcinogenesis is still debated. We report an unusual case of an EBV-associated foveolar gastric dysplasia associated with a focus of EBV-positive low-grade tubular adenocarcinoma, arisen in the context of a lymphocytic-like (EBV-positive) gastritis. The present case offers the unique opportunity to determine whether EBV is an early or late event in gastric cancer development and to evaluate its prevalence in patients with gastric dysplasia. To properly address this question, we investigated EBER expression in a large mono-institutional series of gastric and gastro-esophageal cancers (n = 594) and associated precursor lesions (n = 84). All the selected gastric dysplastic lesions (n = 43) resulted EBV negative. In most cases, EBV is present only in gastric and gastroesophageal junction adenocarcinomas, but not in their precursor lesions. However, the reported case indicates that non-conventional EBV-associated dysplasia may represent a novel histopathological entity in the gastric dysplasia scenario and that EBV could play an early direct role in gastric carcinogenesis.
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Gastric carcinoma with lymphoid stroma diagnosed by endoscopic ultrasound-guided fine-needle aspiration. Clin J Gastroenterol 2021; 14:471-477. [PMID: 33386563 DOI: 10.1007/s12328-020-01300-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 11/12/2020] [Indexed: 10/22/2022]
Abstract
A 78-year-old man with a subepithelial lesion (SEL) in the gastric body and two carcinomas in the gastric antrum was referred to our hospital. Following a diagnosis of SEL, the patient was followed-up by esophagogastroduodenoscopy annually for 4 years. Although the SEL had increased in size over the years, histological evaluation of the forceps biopsies did not reveal any significant findings. We detected a hypoechoic mass in the submucosa by endoscopic ultrasonography, and suspected the lesion to be an aberrant pancreas or mesenchymal tumor. The patient first underwent endoscopic submucosal dissection for the 2 gastric cancers. Histological examination of the resected specimens revealed intramucosal well-differentiated tubular adenocarcinomas. Next, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was performed for the gastric SEL. Aspirated specimens revealed an adenocarcinoma with lymphocyte infiltration. The lesion was diagnosed as a gastric carcinoma with lymphoid stroma (GCLS). Subsequently, he underwent distal gastrectomy, and the surgical specimen was confirmed as GCLS corresponding to preoperative diagnosis. In addition, the adenocarcinoma cells were positive for Epstein-Barr (EB) virus-encoded small RNA-1 by in situ hybridization. Finally, the lesion was diagnosed as GCLS associated with EB virus. Thus, EUS-FNA is advantageous for diagnosing GCLS associated with EB virus.
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8
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Kartika AV, Iizasa H, Ding D, Kanehiro Y, Tajima Y, Kaji S, Yanai H, Yoshiyama H. Application of Biopsy Samples Used for Helicobacter pylori Urease Test to Predict Epstein-Barr Virus-Associated Cancer. Microorganisms 2020; 8:microorganisms8060923. [PMID: 32570907 PMCID: PMC7355529 DOI: 10.3390/microorganisms8060923] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/04/2020] [Accepted: 06/13/2020] [Indexed: 12/12/2022] Open
Abstract
Persistent gastric mucosal damage caused by Helicobacter pylori infection is a major risk factor for gastric cancer (GC). The Epstein-Barr virus (EBV) is also associated with GC. Most patients with EBV-associated GC are infected with H. pylori in East Asia. However, very few reports have described where and when both H. pylori and EBV infect the gastric mucosa. To clarify this, old biopsy samples used for the rapid urease test (RUT) were applied to count EBV genomic DNA (gDNA) copies using DNA probe quantitative polymerase chain reaction. DNA extracted from the gastric biopsy samples of 58 patients with atrophic gastritis was used to analyze the correlation between the degree of atrophic gastritis and the copy number of EBV gDNA. EBV was detected in 44 cases (75.9%), with viral copy numbers ranging from 12.6 to 4754.6. A significant correlation was found between patients with more than 900 copies of EBV gDNA and those with a more severe grade of atrophic gastritis (p = 0.041). This study shows that EBV can be detected in RUT samples in a manner that reduces patient burden.
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Affiliation(s)
- Andy Visi Kartika
- Department of Microbiology, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, Shimane 693-8504, Japan; (A.V.K.); (H.I.); (D.D.); (Y.K.); (S.K.)
- Department of Pathology Anatomy, Faculty of Medicine, University of Muslim Indonesia, Jl. Urip Sumoharjo KM.5, Makassar, Sulawesi 90231, Indonesia
| | - Hisashi Iizasa
- Department of Microbiology, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, Shimane 693-8504, Japan; (A.V.K.); (H.I.); (D.D.); (Y.K.); (S.K.)
| | - Dan Ding
- Department of Microbiology, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, Shimane 693-8504, Japan; (A.V.K.); (H.I.); (D.D.); (Y.K.); (S.K.)
- Department of Neurobiology, Key Laboratory of Craniocerebral Disease, Ningxia Medical University, 1160 Shengli St, Xingqing District, Yinchuan 750004, Ningxia, China
| | - Yuichi Kanehiro
- Department of Microbiology, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, Shimane 693-8504, Japan; (A.V.K.); (H.I.); (D.D.); (Y.K.); (S.K.)
| | - Yoshitsugu Tajima
- Department of digestive and general surgery, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, Shimane 693-8504, Japan;
| | - Shunsuke Kaji
- Department of Microbiology, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, Shimane 693-8504, Japan; (A.V.K.); (H.I.); (D.D.); (Y.K.); (S.K.)
- Department of digestive and general surgery, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, Shimane 693-8504, Japan;
| | - Hideo Yanai
- Department of Clinical Research, National Hospital Organization Kanmon Medical Center, 1-1 Chofu-Sotoura, Shimonoseki, Yamaguchi 752-8510, Japan
- Correspondence: (H.Y.); (H.Y.); Tel.: +81-83-241-1199 (H.Y.); +81-853-20-2146 (H.Y.)
| | - Hironori Yoshiyama
- Department of Microbiology, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, Shimane 693-8504, Japan; (A.V.K.); (H.I.); (D.D.); (Y.K.); (S.K.)
- Correspondence: (H.Y.); (H.Y.); Tel.: +81-83-241-1199 (H.Y.); +81-853-20-2146 (H.Y.)
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Dursun N, Hacıhasanoğlu E, Okçu O, Paşaoğlu E, Leblebici C. Epstein-Barr virus infection in patients with chronic gastritis without Helicobacter pylori infection. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 31:205-210. [PMID: 32343232 DOI: 10.5152/tjg.2020.18850] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS The association of Epstein-Barr virus (EBV) with gastric malignancies has been proven by many studies in the literature. However, information about EBV-associated inflammation/gastritis remains limited. The aim of this study is to establish the prevalence of latent EBV infection in patients with chronic gastritis without H. pylori infection. MATERIALS AND METHODS In this study, 119 patients with gastritis without H. pylori infection were included. Furthermore, 28 patients with H. pylori gastritis were included in the study as a control group. Chromogenic in situ hybridization (EBV-encoded RNA) and immunohistochemistry (LMP-1 antibody) were performed in all 147 cases. The prevalence of EBV and its relationship with age, sex, the affected part of the stomach, the density of inflammation, inflammatory activity, intestinal metaplasia, and atrophy were analyzed. RESULTS In this study, 14 cases showed positive immunostaining for EBV. EBV positivity was seen mostly in the lymphoid tissue (13 cases), but it was also detected at the gastric epithelium (7 cases). The mean age of the patients was 44 years, which was slightly younger than that of the EBV-negative cases (48 years). The inflammation density was higher in EBV-positive cases than the EBV-negative gastritis cases (p=0.002). Intestinal metaplasia was detected in 7% of the cases. EBV-positive cases had a higher incidence of atrophy without intestinal metaplasia (21% vs 3.8% without EBV). CONCLUSION EBV was detected in 12% of the cases with gastritis without H. pylori infection. Endoscopic follow-up may be appropriate for patients with gastritis, who have atrophy without intestinal metaplasia and are H. pylori negative but EBV positive.
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Affiliation(s)
- Nevra Dursun
- Department of Pathology, University of Health Sciences School of Medicine, İstanbul Training and Research Hospital, İstanbul, Turkey
| | | | - Oğuzhan Okçu
- Department of Pathology, Recep Tayyip Erdogan University, Rize Training and Research Hospital, Rize, Turkey
| | - Esra Paşaoğlu
- Department of Pathology, University of Health Sciences School of Medicine, Bagcilar Training and Research Hospital, İstanbul, Turkey
| | - Cem Leblebici
- Department of Pathology, University of Health Sciences School of Medicine, İstanbul Training and Research Hospital, İstanbul, Turkey
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10
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Thirty years of Epstein-Barr virus-associated gastric carcinoma. Virchows Arch 2019; 476:353-365. [PMID: 31836926 DOI: 10.1007/s00428-019-02724-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/18/2019] [Accepted: 11/25/2019] [Indexed: 12/13/2022]
Abstract
Thirty years have passed since a possible association of Epstein-Barr virus (EBV) with gastric carcinoma was reported. We now know EBV-associated gastric carcinoma to be a specific subtype of gastric carcinoma. Global epigenetic methylation and counteraction of the antitumour microenvironment are two major characteristics of this subtype of gastric carcinoma. Recent development of therapeutic modalities for gastric carcinoma, such as endoscopic mucosal dissection and immune checkpoint inhibitor therapy, has made the presence of EBV infection a biomarker for the treatment of gastric carcinoma. This review presents a portrait of EBV-associated gastric carcinoma from initiation to maturity that we define as the 'gastritis-infection-cancer sequence', followed by its molecular abnormalities and interactions with immune checkpoint molecules and the microenvironment. EBV non-coding RNAs (microRNA and circular RNA) and exosomes derived from EBV-infected cells that were previously behind the scenes are now recognized for their roles in EBV-associated gastric carcinoma. The virus utilizes cellular machinery skilfully to control infected cells and their microenvironment. We should thus strive to understand virus-host interactions more fully in the following years to overcome this virus-driven subtype of gastric carcinoma.
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11
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Establishment of a Screening Method for Epstein-Barr Virus-Associated Gastric Carcinoma by Droplet Digital PCR. Microorganisms 2019; 7:microorganisms7120628. [PMID: 31795435 PMCID: PMC6956032 DOI: 10.3390/microorganisms7120628] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 11/26/2019] [Accepted: 11/28/2019] [Indexed: 12/13/2022] Open
Abstract
Background: Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is classified as one of the molecular subtypes of gastric cancer. We used droplet digital polymerase chain reaction (ddPCR) to enable highly sensitive and quantitative detection of EBV. Methods: EBV-DNA load was calculated based on the copy number of the BamH1-W fragment of EBV by ddPCR, and the cut-off value of EBV-DNA load was set. We conducted both ddPCR and EBER1 ISH to examine whether their results coincided in 158 gastric cancer specimens of unknown EBV status. We prepared 26 biopsy specimens and 49 serum samples including EBVaGC and assayed them by ddPCR. Results: The median values of EBV-DNA load for EBVaGC and EBV-negative control were 17.0 and 0.00308, respectively. A cut-off value of 0.032 was determined for which the sensitivity was 1. Among the 158 gastric cancer specimens, 14 lesions were judged as EBV-positive by the 0.032 cut-off value determined by ddPCR. The results of ddPCR and EBER1 ISH were in complete agreement. Even when using a biopsy specimen as a sample for ddPCR, the EBV-DNA load of all EBVaGCs was larger than the cut-off value. Conclusions: We established a new method of diagnosing EBVaGC from tissue samples by ddPCR.
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12
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Ribeiro J, Malta M, Galaghar A, Afonso LP, Libânio D, Medeiros R, Dinis-Ribeiro M, Pimentel-Nunes P, Sousa H. Epstein-Barr virus is absent in gastric superficial neoplastic lesions. Virchows Arch 2019; 475:757-762. [PMID: 31673776 DOI: 10.1007/s00428-019-02670-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 09/19/2019] [Accepted: 09/22/2019] [Indexed: 02/06/2023]
Abstract
Epstein-Barr virus (EBV) has been associated with about 9% of all gastric carcinomas, but its role in gastric carcinogenesis remains unclear since there is lack of evidence of EBV presence in pre-neoplastic lesions of gastric mucosa. This study intends to determine the prevalence of EBV in gastric dysplasia and superficial neoplasia to clarify whether EBV infection is an early or late event in gastric cancer development. This retrospective study included a total of 242 gastric lesions from 199 consecutive patients who were referred for endoscopic resection. The histological classification of lesions includes 137 low- and high-grade dysplasia and 105 superficial carcinomas. EBV infection was investigated by EBER-ISH. Results showed that EBV was not detected in any epithelial cells of any case with dysplasia or superficial carcinomas, although we observed the presence of a small number of EBV-infected lymphocytes in 2.1% of all lesions. These results showed that EBV is not present in gastric dysplasia neither in superficial carcinomas suggesting that EBV carcinogenesis is a late event in well/moderately differentiated gastric carcinogenesis.
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Affiliation(s)
- Joana Ribeiro
- Molecular Oncology & Viral Pathology Group (CI-IPOP), Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. .,Faculty of Medicine of Porto University, FMUP, Rua Al. Prof Hernâni Monteiro, 4200-072, Porto, Portugal.
| | - Mariana Malta
- Molecular Oncology & Viral Pathology Group (CI-IPOP), Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Research Department, Portuguese League Against Cancer (Liga Portuguesa Contra o Cancro-Núcleo Regional do Norte), Estrada interior da Circunvalação 6657, 4200-172, Porto, Portugal
| | - Ana Galaghar
- Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Luís Pedro Afonso
- Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Diogo Libânio
- Gastroenterology Department, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,CINTESIS - Center for Health Technology and Services Research (Centro de Investigação Médica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology & Viral Pathology Group (CI-IPOP), Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Research Department, Portuguese League Against Cancer (Liga Portuguesa Contra o Cancro-Núcleo Regional do Norte), Estrada interior da Circunvalação 6657, 4200-172, Porto, Portugal.,Virology Service, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Mario Dinis-Ribeiro
- Gastroenterology Department, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,CINTESIS - Center for Health Technology and Services Research (Centro de Investigação Médica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Pedro Pimentel-Nunes
- Gastroenterology Department, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,CINTESIS - Center for Health Technology and Services Research (Centro de Investigação Médica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Hugo Sousa
- Molecular Oncology & Viral Pathology Group (CI-IPOP), Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. .,Faculty of Medicine of Porto University, FMUP, Rua Al. Prof Hernâni Monteiro, 4200-072, Porto, Portugal. .,Virology Service, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. .,Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal. .,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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13
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Yanai H, Iizasa H, Chihara D, Murakami T, Nishikawa J, Yoshiyama H. Epstein-Barr virus detection using gastric biopsy specimens after rapid urease test for Helicobacter pylori. Endosc Int Open 2019; 7:E431-E432. [PMID: 30931373 PMCID: PMC6428671 DOI: 10.1055/a-0859-7233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 12/27/2018] [Indexed: 10/27/2022] Open
Affiliation(s)
- Hideo Yanai
- Department of Clinical Research, National Hospital Organization Kanmon Medical Center, Yamaguchi, Japan,Corresponding author Hideo Yanai, MD, PhD Department of Clinical ResearchNational Hospital Organization Kanmon Medical Center1-1 Sotoura, ShimonosekiYamaguchi752-8510 Japan+81832411301
| | - Hisashi Iizasa
- Department of Microbiology, Shimane University School of Medicine, Shimane, Japan
| | - Daisuke Chihara
- Department of Gastroenterology & Hepatology, National Hospital Organization Kanmon Medical Center, Yamaguchi, Japan
| | - Tomoyuki Murakami
- Department of Pathology, National Hospital Organization Kanmon Medical Center, Yamaguchi, Japan
| | - Jun Nishikawa
- Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University School of Medicine, Shimane, Japan
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14
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Nanbo A, Ohashi M, Yoshiyama H, Ohba Y. The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission. Front Microbiol 2018; 9:984. [PMID: 29867885 PMCID: PMC5962739 DOI: 10.3389/fmicb.2018.00984] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 04/26/2018] [Indexed: 01/01/2023] Open
Abstract
Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is closely linked to various lymphoid and epithelial malignancies. Previous studies demonstrated that the efficiency of EBV infection in epithelial cells is significantly enhanced by coculturing them with latently infected B cells relative to cell-free infection, suggesting that cell-to-cell contact-mediated viral transmission is the dominant mode of infection by EBV in epithelial cells. However, a detailed mechanism underlying this process has not been fully understood. In the present study, we assessed the role of transforming growth factor β (TGF-β), which is known to induce EBV's lytic cycle by upregulation of EBV's latent-lytic switch BZLF1 gene. We have found that 5 days of cocultivation facilitated cell-to-cell contact-mediated EBV transmission. Replication of EBV was induced in cocultured B cells both with and without a direct cell contact in a time-dependent manner. Treatment of a blocking antibody for TGF-β suppressed both induction of the lytic cycle in cocultured B cells and subsequent viral transmission. Cocultivation with epithelial cells facilitated expression of TGF-β receptors in B cells and increased their susceptibility to TGF-β. Finally, we confirmed the spontaneous secretion of TGF-β from epithelial cells, which was not affected by cell-contact. In contrast, the extracellular microvesicles, exosomes derived from cocultured cells partly contributed to cell-to-cell contact-mediated viral transmission. Taken together, our findings support a role for TGF-β derived from epithelial cells in efficient viral transmission, which fosters induction of the viral lytic cycle in the donor B cells.
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Affiliation(s)
- Asuka Nanbo
- Department of Cell Physiology, Faculty and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Makoto Ohashi
- Department of Oncology, University of Wisconsin, Madison, WI, United States
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University Faculty of Medicine, Izumo, Japan
| | - Yusuke Ohba
- Department of Cell Physiology, Faculty and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Clinical utility of circulating cell-free Epstein-Barr virus DNA in patients with gastric cancer. Oncotarget 2018; 8:28796-28804. [PMID: 28430637 PMCID: PMC5438692 DOI: 10.18632/oncotarget.15675] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 02/06/2017] [Indexed: 12/12/2022] Open
Abstract
Recent comprehensive molecular subtyping of gastric cancer (GC) identified Epstein-Barr virus (EBV)-positive tumors as a subtype with distinct salient molecular and clinical features. In this study, we aimed to determine the potential utility of circulating cell-free EBV DNA as a biomarker for the detection and/or monitoring of therapeutic response in patients with EBV-associated gastric carcinoma (EBVaGC). The EBV genes-to-ribonuclease P RNA component H1 ratios (EBV ratios) in the GC tumors and plasma samples were determined by quantitative real-time polymerase chain reaction in 153 patients with GC, including 14 patients with EBVaGC diagnosed by the conventional method. Circulating cell-free EBV DNA was detected in 14 patients with GC: the sensitivity and specificity of detection were 71.4% (10/14) and 97.1% (135/139), respectively. Plasma EBV ratios were significantly correlated with the size of EBVaGC tumors, and the plasma EBV DNA detected before surgery in EBVaGC cases disappeared after surgery. Patients with EBVaGC may have a better prognosis, but circulating cell-free EBV DNA had no or little impact on prognosis. In addition, repeated assessment of the plasma EBV ratio in EBVaGC showed a decrease and increase in plasma EBV DNA after treatment and during tumor progression/recurrence, respectively. These results suggest the potential utility of circulating cell-free DNA to reveal EBV DNA for the identification of the EBVaGC subtype and/or for real-time monitoring of tumor progression as well as treatment response in patients with EBVaGC.
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16
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Nanbo A, Kachi K, Yoshiyama H, Ohba Y. Epstein–Barr virus exploits host endocytic machinery for cell-to-cell viral transmission rather than a virological synapse. J Gen Virol 2016; 97:2989-3006. [DOI: 10.1099/jgv.0.000605] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Asuka Nanbo
- Department of Cell Physiology, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo, Japan
| | - Kunihiro Kachi
- Graduate School of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo, Japan
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane, Japan
| | - Yusuke Ohba
- Department of Cell Physiology, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo, Japan
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17
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Buzás GM, Konderák J. Co-infection with Helicobacter pylori and Epstein-Barr virus in benign upper digestive diseases: An endoscopic and serologic pilot study. United European Gastroenterol J 2016; 4:388-94. [PMID: 27403305 PMCID: PMC4924431 DOI: 10.1177/2050640615610265] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 09/14/2015] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Some gastric cancers are Epstein-Barr virus associated. AIM To assess the prevalence of Helicobacter pylori and viral co-infection in benign upper digestive diseases. METHODS One hundred and four outpatients were included in a prospective endoscopic-serologic study. Epstein-Barr virus immunoglobulin G (IgG), immunoglobulin M and viral capsid antigen titres were assayed with an ELISA test. Helicobacter pylori was determined by the modified Giemsa stain and by IgG-chemiluminescence. RESULTS The overall prevalence of Helicobacter pylori was 56.7%. Duodenal ulcer patients were infected in 72.5 % of the cases, with the prevalence being 33.3% in functional dyspepsia (p = 0.0008) and 25.8% in reflux patients (p = 0.0001). Epstein-Barr virus IgG was detected in 70.1% of the whole group, 75% of duodenal ulcer patients, 51.2% of functional dyspepsia patients (p = 0.04) and 51.6% of the reflux disease cases (p = 0.04). Co-infection with both agents was detected in 60% of duodenal ulcer patients, 18.1% of functional dyspepsia (p = 0.00014) and 12.9% of reflux disease patients (p = 0.00012). Anti-viral IgG titre displayed a 31.7 ± 3.0 cut-off index in duodenal ulcer, 20.5 ± 3.5 in functional dyspepsia (p = 0.01) and 21.4 ± 3.6 in reflux cases (p = 0.03). CONCLUSIONS Both Helicobacter pylori and Epstein-Barr virus, and co-infection with these agents, were significantly more prevalent in duodenal ulcer patients than in dyspeptic/reflux patients.
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Affiliation(s)
- György M Buzás
- Ferencváros Health Centre, Gastroenterology, Budapest, Hungary
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18
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Abstract
Background. Helicobacter pylori (HP) infection and nonsteroidal anti-inflammatory drugs (NSAID) use are considered the main risk to develop peptic ulcer disease (PUD). However, PUD also occurs in the absence of HP infection and/or NSAID use. Recently, we have found evidence that Epstein-Barr virus (EBV) reactivation increases the risk to develop premalignant and malignant gastric lesions. Objective. To study a possible association between EBV and PUD. Methods. Antibodies against an EBV reactivation antigen, HP, and the HP virulence factor CagA were measured in sera from 207 Mexican subjects, controls (healthy individuals, n = 129), and PUD patients (n = 78, 58 duodenal and 20 gastric ulcers). Statistical associations were estimated. Results. Duodenal PUD was significantly associated with high anti-EBV IgG titers (p = 0.022, OR = 2.5), while anti-EBV IgA was positively associated with gastric PUD (p = 0.002, OR = 10.1). Conclusions. Our study suggests that EBV reactivation in gastric and duodenal epithelium increases the risk to develop PUD.
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Nishikawa J, Yoshiyama H, Iizasa H, Kanehiro Y, Nakamura M, Nishimura J, Saito M, Okamoto T, Sakai K, Suehiro Y, Yamasaki T, Oga A, Yanai H, Sakaida I. Epstein-barr virus in gastric carcinoma. Cancers (Basel) 2014; 6:2259-74. [PMID: 25386788 PMCID: PMC4276965 DOI: 10.3390/cancers6042259] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 09/27/2014] [Accepted: 10/28/2014] [Indexed: 12/28/2022] Open
Abstract
The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma, all tumor cells harbor the clonal EBV genome. Gastric carcinoma associated with EBV has distinct clinicopathological features, occurs predominately in men and in younger-aged individuals, and presents a generally diffuse histological type. Most cases of EBV-associated gastric carcinoma exhibit a histology rich in lymphocyte infiltration. The immunological reactiveness in the host may represent a relatively preferable prognosis in EBV-positive cases. This fact highlights the important role of EBV in the development of EBV-associated gastric carcinoma. We have clearly proved direct infection of human gastric epithelialcells by EBV. The infection was achieved by using a recombinant EBV. Promotion of growth by EBV infection was observed in the cells. Considerable data suggest that EBV may directly contribute to the development of EBV-associated GC. This tumor-promoting effect seems to involve multiple mechanisms, because EBV affects several host proteins and pathways that normally promote apoptosis and regulate cell proliferation.
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Affiliation(s)
- Jun Nishikawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Hironori Yoshiyama
- Department of Microbiology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo City, Shimane 693-8501, Japan.
| | - Hisashi Iizasa
- Department of Microbiology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo City, Shimane 693-8501, Japan.
| | - Yuichi Kanehiro
- Department of Microbiology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo City, Shimane 693-8501, Japan.
| | - Munetaka Nakamura
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Junichi Nishimura
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Mari Saito
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Takeshi Okamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Kouhei Sakai
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Yutaka Suehiro
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Takahiro Yamasaki
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Atsunori Oga
- Department of Pathology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
| | - Hideo Yanai
- Department of Clinical Research, National Hospital Organization Kanmon Medical Center, 1-1 Sotoura, Chofu, Shimonoseki, Yamaguchi 752-8510, Japan.
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan.
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Martínez-López JLE, Torres J, Camorlinga-Ponce M, Mantilla A, Leal YA, Fuentes-Pananá EM. Evidence of Epstein-Barr virus association with gastric cancer and non-atrophic gastritis. Viruses 2014; 6:301-18. [PMID: 24448220 PMCID: PMC3917444 DOI: 10.3390/v6010301] [Citation(s) in RCA: 36] [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: 08/26/2013] [Revised: 12/08/2013] [Accepted: 01/06/2014] [Indexed: 02/07/2023] Open
Abstract
Different lines of evidence support an association between Epstein-Barr virus (EBV) and gastric cancer (GC). The main understood risk factor to develop GC is infection by Helicobacter pylori (H. pylori), which triggers a local inflammatory response critical for progression from gastritis to GC. The role of EBV in early inflammatory gastric lesions has been poorly studied. A recent study proposed a cutoff value of 2000 EBV particles to identify patients with increased chances of infection of the gastric epithelium, which may favor the inflammatory process. To better understand the role of EBV in cancer progression, we analyzed 75 samples of GC, 147 control samples of non-tumor gastric tissue derived from GC patients and 75 biopsies from patients with non-atrophic gastritis (NAG). A first-round PCR was used for EBV detection in tumor and non-tumor controls and a more sensitive nested PCR for gastritis samples; both PCRs had lower detection limits above the proposed cutoff value. With this strategy 10.67% of GC, 1.3% of non-tumor controls and 8% of gastritis samples were found positive. An EBER1 in situ hybridization showed EBV infection of epithelial cells in GC and in a third of NAG samples, while in the other NAGs infection was restricted to the mononuclear cell infiltrate. EBV-positive GCs were enriched in lace and cribriform patterns, while these rare patterns were not observed in EBV negative samples. Our results support a role for EBV in GC and early precursor lesions, either as directly oncogenic infecting epithelial cells or indirectly as an inflammatory trigger.
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Affiliation(s)
- Juan L E Martínez-López
- Virology and Cancer Research Unit, Federico Gomez Children's Hospital of Mexico, Dr. Marquez No.162, Col. Doctores, Cuauhtemoc, Mexico City D.F. 06720, Mexico.
| | - Javier Torres
- Virology and Cancer Research Unit, Federico Gomez Children's Hospital of Mexico, Dr. Marquez No.162, Col. Doctores, Cuauhtemoc, Mexico City D.F. 06720, Mexico.
| | - Margarita Camorlinga-Ponce
- Virology and Cancer Research Unit, Federico Gomez Children's Hospital of Mexico, Dr. Marquez No.162, Col. Doctores, Cuauhtemoc, Mexico City D.F. 06720, Mexico.
| | - Alejandra Mantilla
- Virology and Cancer Research Unit, Federico Gomez Children's Hospital of Mexico, Dr. Marquez No.162, Col. Doctores, Cuauhtemoc, Mexico City D.F. 06720, Mexico.
| | - Yelda A Leal
- Virology and Cancer Research Unit, Federico Gomez Children's Hospital of Mexico, Dr. Marquez No.162, Col. Doctores, Cuauhtemoc, Mexico City D.F. 06720, Mexico.
| | - Ezequiel M Fuentes-Pananá
- Virology and Cancer Research Unit, Federico Gomez Children's Hospital of Mexico, Dr. Marquez No.162, Col. Doctores, Cuauhtemoc, Mexico City D.F. 06720, Mexico.
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Cárdenas-Mondragón MG, Carreón-Talavera R, Camorlinga-Ponce M, Gomez-Delgado A, Torres J, Fuentes-Pananá EM. Epstein Barr virus and Helicobacter pylori co-infection are positively associated with severe gastritis in pediatric patients. PLoS One 2013; 8:e62850. [PMID: 23638154 PMCID: PMC3634751 DOI: 10.1371/journal.pone.0062850] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Accepted: 03/26/2013] [Indexed: 12/22/2022] Open
Abstract
Background H. pylori infection is acquired during childhood and causes a chronic inflammatory response in the gastric mucosa, which is considered the main risk factor to acquire gastric cancer (GC) later in life. More recently, infection by Epstein-Barr virus (EBV) have also been associated with GC. The role of EBV in early inflammatory responses and its relationship with H. pylori infection remains poorly studied. Here, we assessed whether EBV infection in children correlated with the stage of gastritis and whether co-infection with H. pylori affected the severity of inflammation. Methodology/Principal Findings 333 pediatric patients with chronic abdominal pain were studied. From them, gastric biopsies were taken and inflammation graded according to the Sydney system; peripheral blood was drawn and antibodies against EBV (IgG and IgM anti-VCA) and H. pylori (IgG anti-whole bacteria and anti-CagA) were measured in sera. We found that children infected only by EBV presented mild mononuclear (MN) and none polymorphonuclear (PMN) cell infiltration, while those infected by H. pylori presented moderate MN and mild PMN. In contrast, patients co-infected with both pathogens were significantly associated with severe gastritis. Importantly, co-infection of H. pylori CagA+/EBV+ had a stronger association with severe MN (PR 3.0) and PMN (PR 7.2) cells than cases with single H. pylori CagA+ infection. Conclusions/Significance Co-infection with EBV and H. pylori in pediatric patients is associated with severe gastritis. Even single infections with H. pylori CagA+ strains are associated with mild to moderate infiltration arguing for a cooperative effect of H. pylori and EBV in the gastric mucosa and revealing a critical role for EBV previously un-appreciated. This study points out the need to study both pathogens to understand the mechanism behind severe damage of the gastric mucosa, which could identified children with increased risk to present more serious lesions later in life.
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Affiliation(s)
- María 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), Mexico City, Mexico
| | - Ricardo Carreón-Talavera
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría, CMN Siglo-XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Margarita Camorlinga-Ponce
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría, CMN Siglo-XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Alejandro Gomez-Delgado
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría, CMN Siglo-XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Javier Torres
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría, CMN Siglo-XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Ezequiel M. Fuentes-Pananá
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias (UIMEIP), Hospital de Pediatría, CMN Siglo-XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
- * E-mail:
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Iizasa H, Nanbo A, Nishikawa J, Jinushi M, Yoshiyama H. Epstein-Barr Virus (EBV)-associated gastric carcinoma. Viruses 2013; 4:3420-39. [PMID: 23342366 PMCID: PMC3528272 DOI: 10.3390/v4123420] [Citation(s) in RCA: 141] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The ubiquitous Epstein-Barr virus (EBV) is associated with several human tumors, which include lymphoid and epithelial malignancies. It is known that EBV persistently infects the memory B cell pool of healthy individuals by activating growth and survival signaling pathways that can contribute to B cell lymphomagenesis. Although the monoclonal proliferation of EBV-infected cells can be observed in epithelial tumors, such as nasopharyngeal carcinoma and EBV-associated gastric carcinoma, the precise role of EBV in the carcinogenic progress is not fully understood. This review features characteristics and current understanding of EBV-associated gastric carcinoma. EBV-associated gastric carcinoma comprises almost 10% of all gastric carcinoma cases and expresses restricted EBV latent genes (Latency I). Firstly, definition, epidemiology, and clinical features are discussed. Then, the route of infection and carcinogenic role of viral genes are presented. Of particular interest, the association with frequent genomic CpG methylation and role of miRNA for carcinogenesis are topically discussed. Finally, the possibility of therapies targeting EBV-associated gastric carcinoma is proposed.
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Affiliation(s)
- Hisashi Iizasa
- Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan;
| | - Asuka Nanbo
- Graduate School of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo 060-0812, Japan;
| | - Jun Nishikawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan;
| | - Masahisa Jinushi
- Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan; (J.M.); (H.Y.)
| | - Hironori Yoshiyama
- Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan; (J.M.); (H.Y.)
- Author to whom correspondence should be addressed; ; Tel.: +81-11-706-6073; Fax: +81-11-706-6071
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Shukla SK, Prasad KN, Tripathi A, Ghoshal UC, Krishnani N, Husain N. Expression profile of latent and lytic transcripts of epstein-barr virus in patients with gastroduodenal diseases: a study from northern India. J Med Virol 2012; 84:1289-97. [PMID: 22711358 DOI: 10.1002/jmv.23322] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Epstein-Barr virus (EBV) has been shown to be associated with gastric cancer. However, inconsistent findings have been reported regarding the EBV reactivation in gastric cancer and non-carcinomatous gastric epithelium. Therefore, the aim of the study was to investigate the effect of clinicopathological findings on the expression of different transcripts of EBV in patients with gastric cancer, peptic ulcer, and dyspepsia. A total of 200 adult patients (dyspepsia [120], peptic ulcer [30], gastric cancer [50]) undergoing upper gastrointestinal endoscopy were enrolled. EBV infection was diagnosed with non-polymorphic Epstein-Barr nuclear antigen1 (EBNA1) gene based PCR and confirmed by real-time PCR. The transcripts of EBV were detected by real-time RT-PCR. In patients with gastric cancer and peptic ulcer, EBV DNA was detected more often than in those with dyspepsia (P < 0.05). EBNA1 transcript was detected in all EBV positive cases and its expression was neither associated with disease nor with histopathological findings. The expression of BZLF1 was significantly associated with gastric cancer and peptic ulcer compared to dyspepsia (P < 0.01). BZLF1 expression was also found to be higher in Helicobacter pylori infected patients (P = 0.058). Expression of BARF1 and BcLF1 were significantly higher in gastric epithelium of patients having severe grade chronic inflammation (P = 0.05) and gastric atrophy (P = 0.02), respectively. In conclusion, increased expression of lytic transcripts in patients with gastric cancer, peptic ulcer, gastric atrophy, chronic inflammation and H. pylori infection suggests the association of these factors with EBV reactivation.
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Affiliation(s)
- S K Shukla
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Shukla SK, Prasad KN, Tripathi A, Singh A, Saxena A, Ghoshal UC, Krishnani N, Husain N. Epstein-Barr virus DNA load and its association with Helicobacter pylori infection in gastroduodenal diseases. Braz J Infect Dis 2012. [PMID: 22218519 DOI: 10.1016/s1413-8670(11)70255-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
UNLABELLED Helicobacter pylori and Epstein-Barr virus (EBV) infections are common worldwide. Although H. pylori infection is a major factor in gastroduodenal diseases, its role in association with EBV infection is unknown. OBJECTIVE To study the association of H. pylori infection and EBV DNA load in patients with gastroduodenal diseases. METHODS Biopsy samples were collected from 200 adult patients [non-ulcer dyspepsia (NUD) 100, peptic ulcer disease (PUD) 50, gastric carcinoma (GC) 50] undergoing upper gastrointestinal endoscopy. H. pylori infection was diagnosed by rapid urease test, culture, histopathology, PCR and Q-PCR. EBV DNA was detected by non-polymorphic Epstein-Barr nuclear antigen-1 (EBNA-1) gene based Q-PCR. RESULTS In patients with GC and PUD, EBV DNA was detected more often than NUD (GC versus NUD = 90% versus 37%, p < 0.001; PUD versus NUD = 70% versus 37%, p < 0.001). The dual prevalence of H. pylori infection and EBV DNA was significantly higher in patients with GC and PUD than in those with NUD. Median copy number of EBV DNA was considerably higher in GC and PUD than NUD (p < 0.01). The copy number of EBV DNA was significantly higher in H. pylori infected patients (p = 0.015). The number of ureA gene copies was also found to be significantly higher in PUD and NUD with presence of EBV DNA. However, in GC no significant difference was seen between EBV positive and negative status. CONCLUSION There was a trend for higher EBV DNA load in H. pylori positive individuals suggesting a probable role of H. pylori in modulating the conversion of EBV to its lytic phase.
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Affiliation(s)
- Sanket Kumar Shukla
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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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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Hiejima E, Yasumi T, Kubota H, Ohmori K, Ohshima K, Nishikomori R, Nakase H, Chiba T, Heike T. Gastric ulcer and gastroenteritis caused by Epstein-Barr virus during immunosuppressive therapy for a child with systemic juvenile idiopathic arthritis. Rheumatology (Oxford) 2012; 51:2107-9. [DOI: 10.1093/rheumatology/kes101] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Trimeche M, Ksiâa F, Ziadi S, Mestiri S, Hachana M, Gacem RB, Sriha B, Korbi S. Prevalence and characteristics of Epstein-Barr virus-associated gastric carcinomas in Tunisia. Eur J Gastroenterol Hepatol 2009; 21:1001-7. [PMID: 19491698 DOI: 10.1097/meg.0b013e32831f1f53] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE Epstein-Barr virus (EBV) has been linked to gastric carcinoma (GC) with worldwide geographical variations of prevalence ranging from 1 to 18% of cases. Investigations carried out in north Africa have shown that some EBV-associated types of cancers are common in this area. This study was taken to determine the prevalence of EBV-associated GC in Tunisia. METHODS Ninety-six nonselected GC cases (male/female ratio 1.7/1, mean age 60.9 years, range: 20-88 years) were evaluated for the presence of EBV by polymerase chain reaction as well as by in-situ hybridization for EBV-encoded small RNAs (EBERs) and immunohistochemistry for LMP-1 and EBNA-2 expression. RESULTS EBV was detected by polymerase chain reaction in 36% of cases, whereas EBERs were detected in the tumor cells in only four cases (4.1%). Immunohistochemistry for LMP-1 and EBNA-2 was negative in all cases. The mean age for patients harboring EBERs-positive GC was 55.7 years (range: 52-59 years). All EBERs-positive GC cases were males of advanced clinical stage (pT3-pT4). According to Lauren's classification, two cases were of diffuse histological type and two cases were of intestinal type. In three cases, the tumors have a proximal location and in the remaining case the tumor arises in the antrum. All EBV strains detected from EBV-associated GC were exclusively of type A and D, prototype F, and XhoI-maintained variant. CONCLUSION We conclude that the prevalence of EBV-associated GC in Tunisia is low (4.1%), suggesting that this virus is not an important etiological factor in GC arising in north African populations. The clinicopathological profile of EBV-associated GC in Tunisia did not differ markedly from that found elsewhere.
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Affiliation(s)
- Mounir Trimeche
- Department of Pathology, Farhat Hached Hospital, Sousse 4000, Tunisia.
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Ryan JL, Morgan DR, Dominguez RL, Thorne LB, Elmore SH, Mino-Kenudson M, Lauwers GY, Booker JK, Gulley ML. High levels of Epstein-Barr virus DNA in latently infected gastric adenocarcinoma. J Transl Med 2009; 89:80-90. [PMID: 19002111 PMCID: PMC2612099 DOI: 10.1038/labinvest.2008.103] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Gastric adenocarcinoma is the second leading cause of cancer death worldwide. Epstein-Barr virus (EBV) is present in the malignant cells of approximately 10% of cases. It is unclear whether EBV is being missed in some gastric adenocarcinomas due to insensitive test methods or partial EBV genome loss. In this study, we screened 113 gastric adenocarcinomas from low- and high-incidence regions (United States and Central America) for the presence of EBV using a battery quantitative real-time PCR (Q-PCR) assays targeting disparate segments of the EBV genome (BamH1W, EBNA1, LMP1, LMP2, BZLF1, EBER1) and histochemical stains targeting EBV-encoded RNA (EBER), the latent proteins LMP1 and LMP2, and the lytic proteins BMRF1 and BZLF1. EBV DNA was detected by Q-PCR in 48/75 United States cancers (64%) and in 38/38 Central American cancers (100%), which was a significant difference. EBER was localized to malignant epithelial cells in 8/48 (17%) United States and 3/38 (8%) Central American cancers. Viral loads were considerably higher for EBER-positive vs EBER-negative cancers (mean 162 986 vs 62 EBV DNA copies per 100,000 cells). A viral load of 2000 copies per 100,000 cells is recommended as the threshold distinguishing EBER-positive from EBER-negative tumors. One infected cancer selectively failed to amplify the LMP2 gene because of a point mutation, whereas another cancer had an atypical pattern of Q-PCR positivity suggesting deletion of large segments of the EBV genome. Three different viral latency profiles were observed in the cancers based on constant expression of EBER and focal or variable expression of LMP1 or LMP2, without lytic protein expression. We conclude that EBV DNA levels generally reflect EBER status, and a panel of at least two Q-PCR assays is recommended for sensitive identification of infected cancers.
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Affiliation(s)
- Julie L. Ryan
- Department of Dermatology & Radiation Oncology, University of Rochester Medical Center, Rochester, NY
| | - Douglas R. Morgan
- Department of Gastroenterology, University of North Carolina, Chapel Hill, NC
,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
| | - Ricardo L. Dominguez
- Department of Medicine, Western Regional Hospital, Santa Rosa de Copan, Honduras
| | - Leigh B. Thorne
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC
,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
| | - Sandra H. Elmore
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Gregory Y. Lauwers
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Jessica K. Booker
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC
| | - Margaret L. Gulley
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC
,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
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Schetter AJ, You WC, Lennette ET, Gail MT, Rabkin CS. Association of Epstein-Barr virus antibody levels with precancerous gastric lesions in a high-risk cohort. Cancer Sci 2008; 99:350-4. [PMID: 18201267 PMCID: PMC11159496 DOI: 10.1111/j.1349-7006.2007.00668.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2007] [Revised: 10/12/2007] [Accepted: 10/14/2007] [Indexed: 11/29/2022] Open
Abstract
We evaluated associations between Epstein-Barr virus (EBV) antibody levels and precancerous gastric lesions (chronic atrophic gastritis, intestinal metaplasia, and dysplasia) in 183 subjects from Linqu, China. Immunoglobulin G antibody titers to EBV nuclear antigen (EBNA) and viral capsid antigen (VCA) were determined by two-fold serial dilution using immunofluorescence assays. Histological progression and regression were assessed by gastroscopic examination at the time of phlebotomy and at follow up 2 years later. Antibody titers did not differ significantly among histological diagnoses determined at the time of phlebotomy. However, subjects with dysplasia at follow up had significantly higher geometric mean antibody titers for both anti-VCA and anti-EBNA. Subjects with greater than median antibody levels were more likely to progress between examinations, especially in the subgroup with intestinal metaplasia at the time of phlebotomy (odds ratios [95% confidence intervals]: 5.7 [1.6-20] for anti-EBNA >or=1:320; 3.8 [1.0-15] for anti-VCA >or=1:640). Our findings suggest a possible role for EBV reactivation at an early phase of gastric carcinogenesis.
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Affiliation(s)
- Aaron J Schetter
- Cancer Prevention Fellowship Program, National Cancer Institute, National Institute of Health, 6120 Executive Boulevard, Bethesda, MD 20892-7335, USA
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Xu S, Green M, Kingsley L, Webber S, Rowe D. A comparison of quantitative-competitive and realtime PCR assays using an identical target sequence to detect Epstein-Barr virus viral load in the peripheral blood. J Virol Methods 2006; 137:205-12. [PMID: 16879878 DOI: 10.1016/j.jviromet.2006.06.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2006] [Revised: 06/08/2006] [Accepted: 06/13/2006] [Indexed: 11/22/2022]
Abstract
Monitoring the load of Epstein-Barr virus (EBV) in the peripheral blood by quantitative PCR has been accepted as a useful tool for predicting the onset of EBV related diseases, confirming an EBV disease diagnosis and following the response to treatment interventions. In the present study, the use of a realtime polymerase chain reaction (rt-PCR) assay developed for unpurified cell preparations was examined and the results of the realtime assay were compared to an EBV quantitative-competitive PCR assay (QC-PCR). Both assays use the same target sequence and the same method for determining the standard value for the copy number of EBV genomes present. A comparison of 572 PCR results reveals that the realtime assay gave 5-10-fold higher values than the QC-PCR. Fifty-one results (8.9%) were discordant between the two sets of data. The most commonly encountered discordant result was detection of low amounts of EBV DNA by the rt-PCR assay that were not detected in specimens by QC-PCR. The two assays had a high degree of correlation across the range of load detection allowing clinically relevant threshold values determined in the QC-PCR assay to be inferred for the rt-PCR assay. External normalization of the rt-PCR assay was determined to be an important tool for monitoring the quality and/or quantity of human DNA in the starting material. rt-PCR assays with unpurified cell lysates compare favorably with quantitative-competitive assays and when normalized offer real advantages in specimen preparation, assay manipulations and reproducibility over both quantitative-competitive assays and realtime assays that require purified nucleic acid inputs.
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Affiliation(s)
- Shushen Xu
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, Pennsylvania, United States
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Herrera-Goepfert R, Akiba S, Koriyama C, Ding S, Reyes E, Itoh T, Minakami Y, Eizuru Y. Epstein-Barr virus-associated gastric carcinoma: Evidence of age-dependence among a Mexican population. World J Gastroenterol 2005; 11:6096-103. [PMID: 16273633 PMCID: PMC4436624 DOI: 10.3748/wjg.v11.i39.6096] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate features of Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) among a Mexican population.
METHODS: Cases of primary gastric adenocarcinoma were retrieved from the files of the Departments of Pathology at the Instituto Nacional de Cancerología and the Instituto Nacional de la Nutrición in Mexico City. The anatomic site of the gastric neoplasia was identified, and carcinomas were histologically classified as intestinal and diffuse types and subclassified as proposed by the Japanese Research Society for Gastric Cancer. EBV-encoded small non-polyadenylated RNA-1 (EBER-1) in situ hybridization was conducted to determine the presence of EBV in neoplastic cells.
RESULTS: We studied 330 consecutive, non-selected, primary gastric carcinomas. Among these, there were 173 male and 157 female patients (male/female ratio 1.1/1). EBER-1 was detected in 24 (7.3%) cases (male/female ratio: 1.2/1). The mean age for the entire group was 58.1 years (range: 20-88 years), whereas the mean age for patients harboring EBER-1-positive gastric carcinomas was 65.3 years (range: 50-84 years). Age and histological type showed statistically significant differences, when EBER-1-positive and -negative gastric carcinomas were compared. EBER-1 was detected in hyperplastic- and dysplastic-gastric mucosa surrounding two EBER-1-negative carcinomas, respectively.
CONCLUSION: Among Latin-American countries, Mexico has the lowest frequency of EBVaGC. Indeed, the Mexican population >50 years of age was selectively affected. Ethnic variations are responsible for the epidemiologic behavior of EBVaGC among the worldwide population.
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Affiliation(s)
- Roberto Herrera-Goepfert
- Departamento de Patologia Instituto Nacional de Cancerologia, Av. San Fernando #22, Colonia Seccion XVI, Tlalpan, Mexico DF 14080, Mexico.
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