scholarly journals Overview of Epstein–Barr-Virus-Associated Gastric Cancer Correlated with Prognostic Classification and Development of Therapeutic Options

2020 ◽  
Vol 21 (24) ◽  
pp. 9400
Author(s):  
Valli De Re ◽  
Giulia Brisotto ◽  
Ombretta Repetto ◽  
Mariangela De Zorzi ◽  
Laura Caggiari ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Immune Response ◽  
Epstein Barr Virus ◽  
The Cancer Genome Atlas ◽  
Barr Virus ◽  
Ebv Infection ◽  
Tumor Environment ◽  
Cancer Genome Atlas ◽  
Epstein Barr ◽  
Molecular Phenotypes

Gastric cancer (GC) is a deadly disease with poor prognosis that is characterized by heterogeneity. New classifications based on histologic features, genotypes, and molecular phenotypes, for example, the Cancer Genome Atlas subtypes and those by the Asian Cancer Research Group, help understand the carcinogenic differences in GC and have led to the identification of an Epstein–Barr virus (EBV)-related GC subtype (EBVaGC), providing new indications for tailored treatment and prognostic factors. This article provides a review of the features of EBVaGC and an update on the latest insights from EBV-related research with a particular focus on the strict interaction between EBV infection and the gastric tumor environment, including the host immune response. This information may help increase our knowledge of EBVaGC pathogenesis and the mechanisms that sustain the immune response of patients since this mechanism has been demonstrated to offer a survival advantage in a proportion of patients with GC.

scholarly journals MSI and EBV Positive Gastric Cancer’s Subgroups and Their Link with Novel Immunotherapy

2020 ◽  
Vol 9 (5) ◽  
pp. 1427 ◽  
Author(s):  
Maria Grazia Rodriquenz ◽  
Giandomenico Roviello ◽  
Alberto D’Angelo ◽  
Daniele Lavacchi ◽  
Franco Roviello ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Chromosomal Instability ◽  
Epstein Barr Virus ◽  
Genetic Alterations ◽  
The Cancer Genome Atlas ◽  
Gastric Cancers ◽  
Barr Virus ◽  
Cancer Genome Atlas ◽  
Epstein Barr ◽  
Genome Atlas

Gastric cancers have been historically classified based on histomorphologic features. The Cancer Genome Atlas network reported the comprehensive identification of genetic alterations associated with gastric cancer, identifying four distinct subtypes— Epstein-Barr virus (EBV)-positive, microsatellite-unstable/instability (MSI), genomically stable and chromosomal instability. In particular, EBV-positive and MSI gastric cancers seem responsive to novel immunotherapies drugs. The aim of this review is to describe MSI and EBV positive gastric cancer’s subgroups and their relationship with novel immunotherapy.

scholarly journals Clinical Importance of Epstein–Barr Virus-Associated Gastric Cancer

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 167 ◽  
Author(s):  
Jun Nishikawa ◽  
Hisashi Iizasa ◽  
Hironori Yoshiyama ◽  
Kanami Shimokuri ◽  
Yuki Kobayashi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Carcinoma ◽  
Epstein Barr Virus ◽  
Low Frequency ◽  
Clinical Importance ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Barr Virus ◽  
Cancer Genome Atlas ◽  
Epstein Barr

Epstein–Barr virus-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. EBVaGC has definite histological characteristics similar to gastric carcinoma with lymphoid stroma. Clinically, EBVaGC has a significantly low frequency of lymph node metastasis compared with EBV-negative gastric cancer, resulting in a better prognosis. The Cancer Genome Atlas of gastric adenocarcinomas proposed a molecular classification divided into four molecular subtypes: (1) EBVaGC; (2) microsatellite instability; (3) chromosomal instability; and (4) genomically stable tumors. EBVaGC harbors a DNA methylation phenotype, PD-L1 and PD-L2 overexpression, and frequent alterations in the PIK3CA gene. We review clinical importance of EBVaGC and discuss novel therapeutic applications for EBVaGC.

scholarly journals PD-L1 overexpression in EBV-positive gastric cancer is caused by unique genomic or epigenomic mechanisms

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroshi Nakano ◽  
Motonobu Saito ◽  
Shotaro Nakajima ◽  
Katsuharu Saito ◽  
Yuko Nakayama ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Epstein Barr Virus ◽  
Tumor Tissue ◽  
The Cancer Genome Atlas ◽  
Barr Virus ◽  
Cancer Genome Atlas ◽  
Ifn Γ ◽  
Epstein Barr ◽  
Dual Mechanism ◽  
Irf3 Activation

AbstractEpstein-Barr virus-positive gastric cancer [EBV (+) GC] is a distinct GC subtype with unique genetic and epigenetic aberrations. Here, we examined resected GC samples and publicly available microarray data and The Cancer Genome Atlas (TCGA) database to identify the mechanism underlying overexpression of PD-L1 in EBV (+) GC. We found that high levels of PD-L1 overexpression in EBV (+) GC were caused by focal amplification of CD274. By contrast, relatively high expression of PD-L1 in tumor tissue and infiltrating immune cells correlated with CD8 lymphocyte infiltration and IFN-γ expression via IRF3 activation. Since we reported previously that PD-L1 expression is associated both with the presence of CD8 T cells in the tumor microenvironment and with IFN-γ expression in GC, we examined a database to see whether IFN-γ-associated overexpression of PD-L1 plays a significant role in EBV (+) GC. Immunohistochemical staining showed that expression of the IRF3 signature in clinical GC samples was higher in EBV (+) than in EBV (−) cases. The data presented herein reveal a unique dual mechanism underlying PD-L1 overexpression in EBV (+) GC: high focal amplification of CD274 or IFN-γ-mediated signaling via activation of IRF3.

scholarly journals Validation and calibration of next-generation sequencing to identify Epstein-Barr virus-positive gastric cancer in The Cancer Genome Atlas

2015 ◽  
Vol 19 (2) ◽  
pp. 676-681 ◽  
Author(s):  
M. Constanza Camargo ◽  
Reanne Bowlby ◽  
Andy Chu ◽  
Chandra Sekhar Pedamallu ◽  
Vesteinn Thorsson ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Next Generation Sequencing ◽  
Epstein Barr Virus ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Barr Virus ◽  
Cancer Genome Atlas ◽  
Epstein Barr ◽  
Generation Sequencing ◽  
Genome Atlas

scholarly journals Epstein-Barr Virus-Associated Gastric Cancer: Old Entity with New Relevance

2021 ◽  
Author(s):  
Hugo Manuel Lopes de Sousa ◽  
Joana Patrícia Costa Ribeiro ◽  
Mafalda Basílio Timóteo
Keyword(s):  
Gastric Cancer ◽  
Epstein Barr Virus ◽  
The Cancer Genome Atlas ◽  
Public Health Issue ◽  
Tumor Subtype ◽  
Barr Virus ◽  
Cancer Genome Atlas ◽  
Epstein Barr ◽  
Meta Analyses ◽  
Genome Atlas

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.

Aberrantly methylated-differentially expressed genes and pathways in Epstein–Barr virus-associated gastric cancer

2020 ◽  
Vol 16 (6) ◽  
pp. 187-197
Author(s):  
Jing-jing Jing ◽  
Hao Li ◽  
Ze-yang Wang ◽  
Heng Zhou ◽  
Li-ping Sun ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Differentially Expressed Genes ◽  
Epstein Barr Virus ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Hub Genes ◽  
Barr Virus ◽  
Cancer Genome Atlas ◽  
Epstein Barr ◽  
Genome Atlas

Aim: To identify the methylated-differentially expressed genes (MDEGs) that may serve as diagnostic markers and therapeutic targets in Epstein–Barr virus-associated gastric cancer (EBVaGC) and to explore the methylation-based pathways for elucidating biological mechanisms of EBVaGC. Materials & methods: Gene expression and methylation profiles were downloaded from GEO database. MDEGs were identified by GEO2R. Pathway enrichment analyses were conducted based on DAVID database. Hub genes were identified by Cytoscape, which were further verified by The Cancer Genome Atlas database. Results: A total of 367 hypermethylated, lowly expressed genes were enriched in specific patterns of cell differentiation. 31 hypomethylated, highly expressed genes demonstrated enrichment in regulation of immune system process. After validation using The Cancer Genome Atlas database, seven genes were confirmed to be significantly different hub genes in EBVaGC. Conclusion: EBVaGC-specific MDEGs and pathways can be served as potential biomarkers for precise diagnosis and treatment of EBVaGC and provide novel insights into the mechanisms involved.

scholarly journals Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway

2017 ◽  
Vol 9 (6) ◽  
pp. 574-586 ◽  
Author(s):  
Yuanjun Lu ◽  
Zailong Qin ◽  
Jia Wang ◽  
Xiang Zheng ◽  
Jianhong Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Epstein Barr Virus ◽  
Type I ◽  
Receptor Signaling ◽  
Viral Pathogen ◽  
Infection Period ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

Recognition of viral pathogen-associated molecular patterns by pattern recognition receptors (PRRs) is the first step in the initiation of a host innate immune response. As a PRR, RIG-I detects either viral RNA or replication transcripts. Avoiding RIG-I recognition is a strategy employed by viruses for immune evasion. Epstein-Barr virus (EBV) infects the majority of the human population worldwide. During the latent infection period there are only a few EBV proteins expressed, whereas EBV-encoded microRNAs, such as BART microRNAs, are highly expressed. BART microRNAs regulate both EBV and the host's gene expression, modulating virus proliferation and the immune response. Here, through gene expression profiling, we found that EBV miR-BART6-3ps inhibited genes of RIG-I-like receptor signaling and the type I interferon (IFN) response. We demonstrated that miR-BART6-3p rather than other BARTs specifically suppressed RIG-I-like receptor signaling-mediated IFN-β production. RNA-seq was used to analyze the global transcriptome change upon EBV infection and miR-BART6-3p mimics transfection, which revealed that EBV infection-triggered immune response signaling can be repressed by miR-BART6-3p overexpression. Furthermore, miR-BART6-3p inhibited the EBV-triggered IFN-β response and facilitated EBV infection through targeting the 3′UTR of RIG-I mRNA. These findings provide new insights into the mechanism underlying the strategies employed by EBV to evade immune surveillance.

scholarly journals Epstein-Barr Virus-Positive Cancers Show Altered B-Cell Clonality

mSystems ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Sara R. Selitsky ◽  
David Marron ◽  
Lisle E. Mose ◽  
Joel S. Parker ◽  
Dirk P. Dittmer
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
The Cancer Genome Atlas ◽  
Barr Virus ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Epstein Barr ◽  
Tumor Types ◽  
Genome Atlas

ABSTRACTEpstein-Barr virus (EBV) is convincingly associated with gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. To test the hypothesis that there are additional cancer types with high prevalence of EBV, we determined EBV viral expression in all the Cancer Genome Atlas Project (TCGA) mRNA sequencing (mRNA-seq) samples (n= 10,396) from 32 different tumor types. We found that EBV was present in gastric adenocarcinoma and lymphoma, as expected, and was also present in >5% of samples in 10 additional tumor types. For most samples, EBV transcript levels were low, which suggests that EBV was likely present due to infected infiltrating B cells. In order to determine if there was a difference in the B-cell populations, we assembled B-cell receptors for each sample and found B-cell receptor abundance (P≤ 1.4 × 10−20) and diversity (P≤ 8.3 × 10−27) were significantly higher in EBV-positive samples. Moreover, diversity was independent of B-cell abundance, suggesting that the presence of EBV was associated with an increased and altered B-cell population.IMPORTANCEAround 20% of human cancers are associated with viruses. Epstein-Barr virus (EBV) contributes to gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. We assessed the prevalence of EBV in RNA-seq from 32 tumor types in the Cancer Genome Atlas Project (TCGA) and found EBV to be present in >5% of samples in 12 tumor types. EBV infects epithelial cells and B cells and in B cells causes proliferation. We hypothesized that the low expression of EBV in most of the tumor types was due to infiltration of B cells into the tumor. The increase in B-cell abundance and diversity in subjects where EBV was detected in the tumors strengthens this hypothesis. Overall, we found that EBV was associated with an increased and altered immune response. This result is not evidence of causality, but a potential novel biomarker for tumor immune status.

scholarly journals Epstein-Barr Virus miR-BART17-5p Promotes Migration and Anchorage-Independent Growth by Targeting Kruppel-Like Factor 2 in Gastric Cancer

2020 ◽  
Vol 8 (2) ◽  
pp. 258 ◽  
Author(s):  
Jae Hee Yoon ◽  
Kyoungmi Min ◽  
Suk Kyeong Lee
Keyword(s):  
Gastric Cancer ◽  
Gastric Carcinoma ◽  
Epstein Barr Virus ◽  
The Cancer Genome Atlas ◽  
Sequencing Data ◽  
Ags Cells ◽  
Anchorage Independent Growth ◽  
Barr Virus ◽  
Epstein Barr ◽  
Bart Mirnas

Epstein-Barr virus (EBV) infects more than 90% of the global population and is associated with a variety of tumors including nasopharyngeal carcinoma, Hodgkin lymphoma, natural killer/T lymphoma, and gastric carcinoma. In EBV-associated gastric cancer (EBVaGC), highly expressed EBV BamHI A rightward transcripts (BART) miRNAs may contribute to tumorigenesis with limited viral antigens. Despite previous studies on the targets of BART miRNAs, the functions of all 44 BART miRNAs have not been fully clarified. Here, we used RNA sequencing data from the Cancer Genome Atlas to find genes with decreased expression in EBVaGC. Furthermore, we used AGS cells infected with EBV to determine whether expression was reduced by BART miRNA. We showed that the expression of Kruppel-like factor 2 (KLF2) is lower in AGS-EBV cells than in the AGS control. Using bioinformatics analysis, four BART miRNAs were selected to check whether they suppress KLF2 expression. We found that only miR-BART17-5p directly down-regulated KLF2 and promoted gastric carcinoma cell migration and anchorage-independent growth. Our data suggest that KLF2 functions as a tumor suppressor in EBVaGC and that miR-BART17-5p may be a valuable target for effective EBVaGC treatment.

scholarly journals Clinicopathologic Characteristics of Epstein–Barr Virus-Associated Gastric Cancer Over the Past Decade in Japan

2019 ◽  
Vol 7 (9) ◽  
pp. 305 ◽  
Author(s):  
Yanagi ◽  
Nishikawa ◽  
Shimokuri ◽  
Shuto ◽  
Takagi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Epstein Barr Virus ◽  
Clinicopathologic Characteristics ◽  
Barr Virus ◽  
Ebv Infection ◽  
The Past ◽  
Lymphoid Stroma ◽  
Human Herpes Virus ◽  
Epstein Barr

: Epstein–Barr virus (EBV) is a ubiquitous human herpes virus, but related with several types of malignancies. Among EBV-related malignancies, EBV-associated gastric carcinoma (EBVaGC) has the largest patient’s number. We screened for EBV infection in 1067 GC lesions of 1132 patients who underwent surgical resection from 2007 to 2017 in Japan and examined clinicopathological features of EBVaGC. EBV infection was detected by in situ hybridization with EBV-encoded small RNA 1(EBER-1 ISH). EBV was infected in 80 GC lesions (7.1%). Mean age was significantly lower in patients with EBVaGC than with EBV-negative GC. EBVaGC was more frequent in men than in women. EBVaGC was found twice as frequent in the upper or middle stomach as in the lower stomach. Early EBVaGC was more frequent, and submucosally invaded cases were dominant. The presence of lymphatic vessel invasion was less in EBVaGC, but frequency of lymph node metastasis was similar. Carcinoma with lymphoid stroma (CLS) was found in 3.8% (43/1132) of all lesions with 60.5% of EBV positivity. The synchronous or metachronous multiple GC was frequent in EBVaGC. We clarified clinicopathologic characteristics of EBVaGC over the past decade in Japan. EBV infection should be examined in gastric cancer cases showing these characteristics.

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