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Novel Epstein-Barr virus immunoglobulin G-based approach for the specific detection of nasopharyngeal carcinoma

Abdulamir AS, Hafidh RR, Abu Bakar F, Abbas K

Am J Otolaryngol, 2010 Nov-Dec;31(6):410-7.
PMID: 20015794 DOI: 10.1016/j.amjoto.2009.06.006

PURPOSE: This study was designed to find a reliable Epstein-Barr virus (EBV) immunoglobulin (Ig) G-based diagnostic/screening test for nasopharyngeal carcinoma (NPC) able to demarcate between the NPC-related seropositivity of EBV IgG antibodies and that of other head and neck cancer (HNCA) and control groups. The NPC-associated immunosuppression affects EBV IgA much more than IgG, leading to inconsistent detection of NPC using EBV IgA antibodies.
MATERIALS AND METHODS: One hundred twenty-two HNCA patients, 42 NPC, 66 laryngeal carcinoma, and 14 hypopharyngeal carcinoma and 3 groups of 100 control subjects were enrolled in this study. Enzyme-linked immunosorbent assay (ELISA) was used to find a specific cutoff value for the NPC-related seropositivity of EBV IgG antibodies.
RESULTS: NPC group showed higher serum level of EBV IgG antibodies than control and other HNCA groups (P < .05). However, the traditional cutoff value, mean + 2 SDs of control subjects, failed to demarcate the seropositives of NPC patients from those of healthy population (P > .05). The new cutoff value, mean + 2 SDs of the seropositives group of control subjects who had already been grouped by the traditional cutoff value, proved successful. It succeeded to demarcate between the NPC-related EBV IgG seropositivity and that issued from the persistent, latent, or reactivated EBV infection in the population (P < .05). The sensitivity/specificity of NPC detection by the new cutoff-based ELISA kit, 76.19% and 86%, was close or higher than that of EBV IgA antibodies.
CONCLUSION: EBV IgG-based ELISA could be used for the diagnosis of NPC using a new cutoff threshold that excludes the population baseline of EBV IgG seropositivity.

Matched MeSH terms: Epstein-Barr Virus Infections/immunology
pSTAT3 and MYC in Epstein-Barr virus-positive diffuse large B-cell lymphoma

Teoh SH, Khoo JJ, Abdul Salam DSD, Peh SC, Cheah SC

Malays J Pathol, 2019 Dec;41(3):273-281.
PMID: 31901912

INTRODUCTION: Epstein-Barr Virus (EBV) is associated with several B-cell non-Hodgkin's lymphoma (NHL), but the role of EBV in diffuse large B-cell lymphoma (DLBCL) is poorly defined. Several studies indicated the expression of phosphorylated STAT3 (pSTAT3) is predominant in EBV(+)- DLBCL, of which its activated form can promote the downstream oncogenes expression such as c-MYC. c-MYC gene rearrangements are frequently found in aggressive lymphoma with inferior prognosis. Furthermore, EBV is a co-factor of MYC dysregulation. JAK1/STAT3 could be the downstream pathway of EBV and deregulates MYC. To confirm the involvement of EBV in JAK1/ STAT3 activation and MYC deregulation, association of EBV, pSTAT3 and MYC in EBV(+)- DLBCL cases were studied. The presence of pSTAT3 and its upstream proteins: pJAK1 is identify to delineate the role of EBV in JAK1/STAT3 pathway.
MATERIALS AND METHODS: 51 cases of DLBCL paraffin-embedded tissue samples were retrieved from a single private hospital in Kuala Lumpur, Malaysia. EBER-ISH was performed to identify the EBV expression; ten EBV(+)-DLBCL cases subjected to immunohistochemistry for LMP1, pJAK1, pSTAT3 and MYC; FISH assay for c-MYC gene rearrangement.
RESULTS: Among 10 cases of EBV(+)-DLBCL, 90% were non-GCB subtype (p=0.011), 88.9% expressed LMP1. 40% EBV(+)-DLBCL had pJAK1 expression.
CONCLUSION: 66.7% EBV(+)-DLBCL showed the positivity of pSTAT3, which implies the involvement of EBV in constitutive JAK/STAT pathway. 44.5% EBV(+)-DLBCL have co-expression of pSTAT3 and MYC, but all EBV(+)-DLBCL was absence with c-MYC gene rearrangement. The finding of clinical samples might shed lights to the lymphomagenesis of EBV associated with non-GCB subtypes, and the potential therapy for pSTAT3-mediated pathway.

Matched MeSH terms: Epstein-Barr Virus Infections/virology*
Extranodal NK/T-cell lymphoma mimicking Crohn's colitis

Wan Ahmad Kammal WS, Mohd Rose I, Md Zin RR, Raja Ali RA, Masir N

Malays J Pathol, 2019 Aug;41(2):195-199.
PMID: 31427556

INTRODUCTION: Extranodal NK/T cell lymphoma is a rare tumour, typically involving the upper aerodigestive tract. Even rarer is primary extranasal disease involving the skin, testis, soft tissue and gastrointestinal tract.
CASE REPORT: We report a case of a 46-year-old Chinese male who presented with six months history of abdominal pain, weight loss and rectal bleeding. Diagnostic colonoscopy revealed multiple aphthous ulcers within the ileo-caecal region and distal transverse colon, separated by normal mucosa, mimicking skip lesions of Crohn's colitis. Computer topography (CT) scan of the abdomen showed multiple circumferential thickenings involving predominantly the right colon. A clinical diagnosis of colonic Crohn's disease with possible perforation was made. An extended right hemicolectomy was performed due to uncontrolled rectal bleeding. Histopathology examination of the colon showed infiltration by malignant lymphoid cells associated with necrosis, angiocentricity and angiodestruction. Immunohistochemical studies confirmed T-cell monoclonality, presence of cytotoxic granules and Epstein-Barr virus (EBV) infection. A diagnosis of extranodal NK/T cell lymphoma of the colon was made.
DISCUSSION: These findings highlight that colonic NK/T cell lymphoma may clinically mimic other benign inflammatory lesions and should be one of the differential diagnoses in patients presenting with gastrointestinal lesions. The final diagnosis is only possible with appropriate histological and immunohistochemical studies.

Matched MeSH terms: Epstein-Barr Virus Infections
Fulltext Nasopharyngeal carcinoma among the Bidayuh of Sarawak, Malaysia: History and risk factors

Linton RE, Daker M, Khoo AS, Choo DCY, Viljoen M, Neilsen PM

Oncol Lett, 2021 Jul;22(1):514.
PMID: 33986874 DOI: 10.3892/ol.2021.12775

Nasopharyngeal carcinoma (NPC) is a cancer of the epithelial cells lining the nasopharynx. The incidence of NPC has a distinct geographical distribution, mainly affecting the Chinese population of Southern China. In Malaysia, this cancer is exceptionally prevalent among males. There is a high incidence rate of NPC among the Bidayuh natives in Sarawak, Malaysia. Other than epidemiology reports, there has not been an article describing plausible cancer risk factors contributing to NPC within this native group. Researchers are still trying to understand the reasons the Bidayuh and Southern Chinese are highly susceptible to NPC. This article discusses the risk factors of developing NPC: Epstein-Barr virus infection, genetic predisposition, diet, environmental exposure and tobacco smoking. There is a need to improve the understanding of the role of risk factors to identify new ways to prevent cancer, especially among high-risk groups.

Matched MeSH terms: Epstein-Barr Virus Infections
Down-regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV-associated nasopharyngeal carcinoma

Yap LF, Velapasamy S, Lee HM, Thavaraj S, Rajadurai P, Wei W, et al.

J Pathol, 2015 Feb;235(3):456-65.
PMID: 25294670 DOI: 10.1002/path.4460

Undifferentiated nasopharyngeal carcinoma (NPC) is a highly metastatic disease that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the contribution of lysophosphatidic acid (LPA) signalling to the pathogenesis of NPC. Here we demonstrate two distinct functional roles for LPA in NPC. First, we show that LPA enhances the migration of NPC cells and second, that it can inhibit the activity of EBV-specific cytotoxic T cells. Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor 5 (LPAR5), is down-regulated in primary NPC tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines. Furthermore, we found that EBV infection or ectopic expression of the EBV-encoded LMP2A was sufficient to down-regulate LPAR5 in NPC cell lines. Our data point to a central role for EBV in mediating the oncogenic effects of LPA in NPC and identify LPA signalling as a potential therapeutic target in this disease.

Matched MeSH terms: Epstein-Barr Virus Infections/physiopathology*
Dual variant of Epstein-Barr virus in Hodgkin/Reed-Sternberg cells: single-cell PCR study on latent membrane protein-1 gene

Kim LH, Peh SC, Poppema S

Int J Cancer, 2003 Nov 1;107(2):250-5.
PMID: 12949802

Isolation of single cells permits analysis of DNA or RNA from individual cells among heterogeneous populations. This technique is particularly useful in the study of classical Hodgkin's lymphoma (cHL) due to the scarcity of H/RS tumor cells among large numbers of reactive leukocytes. In a previous study, we found a high frequency of dual LMP-1 variant (concurrent presence of deleted and nondeleted variants) in cHL from whole-tissue sections. For the present study, we applied a single-cell isolation technique to determine the LMP-1 oncogene variant in EBV-associated H/RS cells. Five cases of EBV-infected cHL, containing nondeleted (n=1), deleted (n=1) and dual infection (n=3) based on whole-tissue section analysis, were selected for study. Paraffin-embedded tissue sections were stained with antibody to LMP-1 and positively stained H/RS cells isolated using a semiautomated micromanipulator. Each isolated single cell was subjected to PCR for amplification of the LMP-1 gene flanking the 30 bp deletion region and Xho1 restriction site. Cases with either nondeleted variant or the deleted variant showed similar LMP-1 variant expression in isolated single H/RS cells. However, 1 of the 3 cases with dual variants showed only the deleted variant in H/RS cells. The other 2 cases showed mixed patterns of deleted, nondeleted and dual LMP-1 variants in isolated single H/RS cells. All cases showed loss of the Xho1 restriction site, with the exception of the case with nondeleted LMP-1. Results of single-H/RS cell analysis of the Xho1 restriction site concur with those of whole-tissue section amplification. A mixed pattern of LMP-1 variants was observed in isolated H/RS cells, and it is speculated that this is due to the accumulation of mutation and deletion events.

Matched MeSH terms: Epstein-Barr Virus Infections/virology
High frequency of EBV association and 30-bp deletion in the LMP-1 gene in CD56 lymphomas of the upper aerodigestive tract

Tai YC, Kim LH, Peh SC

Pathol. Int., 2004 Mar;54(3):158-66.
PMID: 14989738

Natural killer (NK)/T-cell lymphomas are frequently associated with Epstein-Barr virus (EBV), and usually lack TCR gene rearrangement. Studies from Asia have reported frequent deletion in the LMP-1 gene in EBV-associated nasopharyngeal carcinoma (NPC). The present study aims to investigate LMP-1 and TCRgamma gene status in upper aerodigestive tract lymphomas. A total of 43 cases were classified into T-, B-, and NK/T-cell tumors based on the phenotype expressions of CD3(+)/CD20(-)/CD56(-), CD3(-)/CD20(+)/CD56(-), and CD3(+)/CD20(-)/CD56(+), respectively. The presence of EBV in the tumor was confirmed by EBV early RNA-in situ hybridization. LMP-1 gene deletion and TCR gamma gene rearrangement were analyzed by polymerase chain reaction on paraffin-embedded tissues. There were 20 NK/T-, eight T-, and 15 B-cell phenotype lymphomas in the present series, and EBV was detected in 19 (95%), two (25%), and three (20%) cases in the respective groups. All EBV+ cases carried 30-bp deletion in the LMP-1 gene, and two of the NK/T-cell cases were infected by both the wild type and deleted strains. Five (25%) of the NK/T-cell phenotype lymphomas showed rearranged TCR gamma gene. The present study revealed a high frequency of EBV association, and a high frequency of 30-bp deletion in the LMP-1 gene in the virus in the present series of lymphoma. The NK/T-phenotype lymphomas are comprised of both NK-cell and cytotoxic T-lymphocyte-derived tumors.

Matched MeSH terms: Epstein-Barr Virus Infections/genetics*
Epstein-Barr virus-encoded latent membrane protein-1 upregulates 14-3-3σ and Reprimo to confer G(2)/M phase cell cycle arrest

Yeo KS, Mohidin TB, Ng CC

C. R. Biol., 2012 Dec;335(12):713-21.
PMID: 23312294 DOI: 10.1016/j.crvi.2012.11.002

Epstein-Barr virus (EBV) is a ubiquitous tumor-causing virus which infects more than 90% of the world population asymptomatically. Recent studies suggest that LMP-1, -2A and -2B cooperate in the tumorigenesis of EBV-associated epithelial cancers such as nasopharygeal carcinoma, oral and gastric cancer. In this study, LMPs were expressed in the HEK293T cell line to reveal their oncogenic mechanism via investigation on their involvement in the regulation of the cell cycle and genes that are involved. LMPs were expressed in HEK293T in single and co-expression manner. The transcription of cell cycle arrest genes were examined via real-time PCR. Cell cycle progression was examined via flow cytometry. 14-3-3σ and Reprimo were upregulated in all LMP-1 expressing cells. Moreover, cell cycle arrest at G(2)/M progression was detected in all LMP-1 expressing cells. Therefore, we conclude that LMP-1 may induce cell cycle arrest at G(2)/M progression via upregulation of 14-3-3σ and Reprimo.

Matched MeSH terms: Epstein-Barr Virus Infections