Epstein-Barr virus-associated gastric adenocarcinoma in Taiwan

doi:10.1016/0046-8177(95)90056-X

Human Pathology

Volume 26, Issue 3, March 1995, Pages 267-271

https://doi.org/10.1016/0046-8177(95)90056-X Get rights and content

Abstract

Fifty-five gastric carcinoma tumors from Chinese patients in Taiwan, including 40 tubular type (one lymphoepthelioma-like carcinoma subtype), eight signet ring cell type, one papillary type, and six mucinous type gastric carcinomas, were investigated for the presence of Epstein-Barr virus (EBV) transcripts by in situ hybridization using fluorescein-conjugated EBV oligonucleotides for EBERs (Epstein-Barr virus early RNAs) expression and the polymerase chain reaction for viral DNA. Epstein-Barr virus was detected in six of 55 lesions (11%), a significantly lower proportion than has been observed in a North American series. Epstein-Barr virus involvement was more common among male patients. Epstein-Barr virus DNA and its EBERs were specifically present within gastric carcinoma and adjacent dysplastic cells but were absent in surrounding lymphocytes and normal gastric mucosa. Epstein-Barr virus DNA and EBERs were found in one sample of lymphoepithelioma-like carcinoma (LELC) and five specimens of typical gastric adenocarcinoma. Among the EBV-positive gastric adenocarcinomas, four were tubular type of varied differentiation and one was signet ring cell type. Furthermore, we evaluated the expression of the latent membrane protein (LMP) with monoclonal antibodies. We found that LMP was expressed in two EBVpositive samples. In addition, the presence of the EBV receptor was studied by probing samples with CD21 monoclonal antibody. Epstein-Barr virus receptor was not detected in any sample. Southern blot analysis indicated single clonal proliferation of tumor cells. These findings confirm and extend the results of Shibata et al. They also indicate that EBV infection might be related to oncogenesis not only in rare gastric cancers that resemble nasopharyngeal lymphoepithelioma but also in typical gastric adenocarcinoma.

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Cited by (99)

Estimating the Global Burden of Epstein-Barr Virus–Associated Gastric Cancer: A Systematic Review and Meta-Analysis
2023, Clinical Gastroenterology and Hepatology
Evidence suggests that a fraction of new gastric cancer cases may be etiologically associated with Epstein-Barr virus (EBV), a known carcinogenic agent. We aimed to systematically explore the proportion of EBV-positive gastric cancer.
We did a systematic review (PROSPERO CRD42020164473) from January 1990 to August 2021. For each country and geographical region with available data, pooled prevalence and corresponding 95% confidence intervals (CIs) of EBV in gastric tumors were calculated for 3 subtypes of gastric adenocarcinoma (conventional adenocarcinoma, lymphoepithelioma-like gastric carcinoma, and remnant/stump carcinoma). For conventional adenocarcinoma, prevalence ratios (PRs) were presented for sex, Lauren’s classification, gastric cancer stage, and anatomical location of the stomach.
In 220 eligible studies including over 68,000 cases of conventional gastric adenocarcinoma, EBV prevalence in tumor cells was 7.5% (95% CI, 6.9%–8.1%) and was higher in men compared with women (PR, 2.1; 95% CI, 1.9–2.4), in diffuse type compared with intestinal type (PR, 1.3; 95% CI, 1.1–1.5), and in the proximal region compared with the distal region (PR, 2.5; 95% CI, 2.0–3.1). There was no difference in EBV prevalence by gastric cancer stage. EBV prevalence was 75.9% (95% CI, 62.8%–85.5%) among lymphoepithelioma-like gastric carcinoma and 26.3% (95% CI, 22.2%–32.0%) among remnant or stump carcinoma.
Assuming a causal association between EBV and gastric cancer, our findings, when applied to the GLOBOCAN 2020 gastric cancer incidence, suggest that primary prevention such as the development of an effective EBV vaccine might prevent 81,000 EBV-associated gastric cancer cases worldwide annually.
Hypoxia-induced ebv-circLMP2A promotes angiogenesis in EBV-associated gastric carcinoma through the KHSRP/VHL/HIF1α/VEGFA pathway
2022, Cancer Letters
Citation Excerpt :
EBVaGC is an independent subtype of GC, accounting for approximately 10% of GC and has unique genomic phenotypes, molecular characteristics, and clinicopathological characteristics compared with EBV-negative GC (EBVnGC) [3]. EBV was positive in all infected GC cells and adjacent dysplastic epithelial cells but negative in surrounding normal epithelial cells and lymphocytes, highlighting the essential roles of EBV in the development of EBVaGC [4,5]. Currently, the most studied EBV-related oncogenic molecule is EBV-encoded LMP1, but EBV does not express LMP1 in EBVaGC, prompting us to look for new EBV-related oncogenic molecules.
EBV-encoded circular RNA LMP2A (ebv-circLMP2A) was found to be expressed in EBV-associated gastric carcinoma (EBVaGC) and associated with distant metastasis and poor prognosis. Angiogenesis is a key step in tumor invasion and metastasis and plays a crucial role in tumor progression. However, it is unclear whether and how ebv-circLMP2A is involved in angiogenesis. In this study, we showed that MVD, HIF1α, and VEGFA expression was increased in EBVaGC mouse xenografts with high expression of ebv-circLMP2A. The expression of ebv-circLMP2A was positively correlated with MVD, HIF1α, and VEGFA expression in clinical samples of EBVaGC. Knockdown of ebv-circLMP2A repressed tube formation and migration of HUVECs and decreased VEGFA and HIF1α expression in cancer cells under hypoxia, while ectopic expression of ebv-circLMP2A reversed these effects. Additionally, knockdown of HIF1α blocked the upregulation of ebv-circLMP2A by hypoxia, and ebv-circLMP2A interacted with KHSRP to enhance KHSRP-mediated decay of VHL mRNA, leading to the accumulation of HIF1α under hypoxia. There was a positive feedback loop between HIF1α and ebv-circLMP2A that promotes angiogenesis under hypoxia. ebv-circLMP2A was essential in regulating tumor angiogenesis in EBVaGC and might provide a valuable therapeutic target for EBVaGC.
EBV down-regulates COX-2 expression via TRAF2 and ERK signal pathway in EBV-associated gastric cancer
2019, Virus Research
Citation Excerpt :
However, LMP1 expression is rarely described in EBVaGC, and it was mentioned in a review by Ribeiro J et al. in 2017 that LMP1 was found to be present in only 10% (21/199) of EBVaGC cases (Ribeiro et al., 2017). Shin et al. (1996) and Ham et al.(Harn et al., 1995) reported 3/6 and 2/12 cases of LMP1 positive expression in EBV positive gastric cancer, respectively. Further investigation about the role of LMP1 in EBVaGC should be studied, because some authors believe that the low expression of LMP1 in EBVaGC is due to technical limitations (Imai et al., 1994; Shin et al., 1996), and other have shown that LMP1 expression can indeed be inhibited in gastric cancer to help tumor cells escape the immune surveillance of the host immune system (Sheu et al., 1998).
Epstein-Barr virus-associated gastric cancer (EBVaGC) accounts for nearly 10% of gastric cancer. Cyclooxygenase-2 (COX-2) plays a crucial role in cancer progression. However, there is no experimental study on the regulation mechanism of EBV on COX-2 in EBVaGC. To understand more about the tumorigenic mechanism of EBVaGC, the study investigated the role of EBV encode latent membrane protein LMP1 and LMP2A in the regulation of COX-2. The expression of COX-2 was examined in EBVaGC and EBV negative gastric cancer (EBVnGC) cell lines. The plasmids were transfected in SGC7901 to overexpress LMP1/2A. Small interfering RNA (si-RNA) targeting LMP1/2A in GT38 and targeting TRAF2 in SGC7901 were used to detect the expression of COX-2. Furthermore, si-ERK1/2 and the MEK inhibitor PD0325901 were used to investigate whether p-ERK participate in the regulation of COX-2 in SGC7901. The overexpression of LMP1 or LMP2A in SGC7901 down-regulates both COX-2 and TRAF2 expression, and knockdown of LMP1 or LMP2A in GT38 resulted in a certain recovery of COX-2 and TRAF2 expression. Moreover, si-TRAF2 indicated that a sharp down-regulation of COX-2. And the decrease of p-ERK also mediates the inhibitory effect of LMP1 on COX-2. In summary, overexpression of LMP1 and LMP2A inhibits COX-2, which is mediated by a decrease of TRAF2, and p-ERK is involved in the inhibition of COX-2 by LMP1 in gastric cancer.
Synchronous adenocarcinoma and lymphoepithelioma-like carcinoma in the stomach: A case presentation and literature review
2012, Revista de Gastroenterologia de Mexico
El cáncer gástrico es una de las principales causas de muerte en el mundo. En Venezuela, las neoplasias gástricas representan 37% de todos los tumores malignos del sistema digestivo, pero el carcinoma tipo linfoepitelioma, sólo se presenta entre 1,6% y 3,1% de los casos. También es rara la presentación de lesiones tumorales sincrónicas. Al respecto se expone el caso clínico, el primero en este país, de un varón con 2 lesiones tumorales sincrónicas. Las lesiones lucían como incipientes, no obstante, el estudio histológico mostró 2 neoplasias malignas de estirpe epitelial: adenocarcinoma bien diferenciado y carcinoma tipo linfoepitelioma.
Gastric cancer is one of the main causes of death in the world. In Venezuela, gastric tumors represent 37% of all malignant tumors of the digestive system, but only 1,6% to 3,1% of these cases are lymphoepithelioma-like carcinoma. Synchronous neoplastic lesions are also rare. The clinical case presented herein, a man with two synchronous tumor lesions, is the first of its kind in this country. Despite their incipient aspect, the histologic study reported two malignant tumors of epithelial origin: well-differentiated adenocarcinoma and lymphoepithelioma-like carcinoma.
Differences in Gastric Carcinoma Microenvironment Stratify According to EBV Infection Intensity: Implications for Possible Immune Adjuvant Therapy
2013, PLoS Pathogens
Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC – high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV.
Clinical outcomes of Epstein–Barr virus (EBV)-associated metastatic and locally advanced unresectable gastric cancers (GCs) in patients receiving first-line fluoropyrimidine and platinum (FP) doublet chemotherapy
2024, Gastric Cancer

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^☆: Supported by grants from the National Science Council (NSC 83-0412-B-016-101) and the Department of Health (DOH 83-HR-203), Taiwan, Republic of China.

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Original contributionEpstein-Barr virus-associated gastric adenocarcinoma in Taiwan☆

Abstract

J Mol Biol

Cell

Cell

Nasopharyngeal carcinoma: Presence of Epstein-Barr genomes in separated epithelial cells of tumors in patients from Singapore, Tunisia, and Kenya

Int J Cancer

Correlation of the expression of Epstein-Barr virus latent membrane protein and in situ hybridization with biotinylated BamHI-W probes in Hodgkin's disease

Am J Pathol

EBV DNA in biopsies of Burkitt tumors and anaplastic carcinoma of the nasopharynx

Nature

Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction

Mod Pathol

Epstein-Barr viral sequences are commonly present in the carcinoma cells of gastric lymphoepithelioma-like carcinoma

Am J Pathol

Original contribution
Epstein-Barr virus-associated gastric adenocarcinoma in Taiwan☆