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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 3  |  Page : 583-586

Role of human Cytomegalovirus in the etiology of nasopharyngeal carcinoma


1 Molecular Diagnostics and Personalized Therapeutics Unit, University of Hail; Department of Pathology, College of Medicine, University of Hail, Hail, Kingdom of Saudi Arabia; Department of Histopathology and Cytology, FMLS, University of Khartoum, Khartoum, Sudan
2 Department of Histopathology and Cytology, Faculty of Medical Laboratory Science, Sudan University for Science and Technology, Khartoum, Sudan
3 Molecular Diagnostics and Personalized Therapeutics Unit, University of Hail; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, Kingdom of Saudi Arabia
4 Department of Pathology, College of Medicine, University of Hail, Hail, Kingdom of Saudi Arabia
5 Department of Anatomy and Histology, College of Medicine, University of Hail, Hail, Kingdom of Saudi Arabia

Date of Web Publication12-Jun-2018

Correspondence Address:
Dr. Hussain Gadelkarim Ahmed
Department of Pathology, College of Medicine, University of Hail, Hail 2440, Kingdom of Saudi Arabia

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.176175

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 > Abstract 


Objective: The purpose of this study was to identify human Cytomegalovirus (HCMV) in tissue blocks obtained from patients with nasopharyngeal carcinoma (NPC).
Materials and Methods: Formalin-fixed paraffin wax processed NPC tissue were obtained from 150 tissue blocks and retrospectively investigated for the presence of HCMV using polymerase chain reaction.
Results: Of the 150 NPC tissue specimens, HCMV was identified in 53/150 (35.3%) of the samples. Out of the 53 samples infected with HCMV, 33/97 (34%) were among males and 20/53 (37.7%) were among females. Of the 53 positive samples, 36/53 (68%) were found to harbor Epstein–Barr virus (EBV).
Conclusion: The present study has shown a relatively considerable association between HCMV and NPC. The great majority of samples sheltering HCMV were also found to hide EBV, which proposes the potentiality of EBV over HCMV.

Keywords: Human Cytomegalovirus, nasopharyngeal carcinoma, Sudan


How to cite this article:
Ahmed HG, Suliman RA, Ashankyty IM, Albieh ZA, Warille AA. Role of human Cytomegalovirus in the etiology of nasopharyngeal carcinoma. J Can Res Ther 2018;14:583-6

How to cite this URL:
Ahmed HG, Suliman RA, Ashankyty IM, Albieh ZA, Warille AA. Role of human Cytomegalovirus in the etiology of nasopharyngeal carcinoma. J Can Res Ther [serial online] 2018 [cited 2021 Jan 27];14:583-6. Available from: https://www.cancerjournal.net/text.asp?2018/14/3/583/176175




 > Introduction Top


The incidence of nasopharyngeal carcinoma (NPC) is noticeably higher in some countries and lower in others. Higher incidences have been found in native and foreign-born Chinese, Southeast Asians, North Africans, and native people of the Arctic region.[1] The 2005 classification of the World Health Organization divides NPC on a pathological basis into three histological subtypes: Keratinizing squamous cell carcinoma; nonkeratinizing carcinoma, which can be further divided into differentiated and undifferentiated subtypes; and basaloid squamous cell carcinoma. Undifferentiated nonkeratinizing NPC is the most common type of NPC and is strongly associated with the Epstein–Barr virus (EBV).[2] Besides EBV, there are many etiological factors include genetic susceptibility, consumption of food (in particular salted fish) containing carcinogenic volatile nitrosamines.[3],[4]

Infections with certain viruses, bacteria, and parasites are one of the biggest and preventable causes of cancer worldwide.[5] Human Cytomegalovirus (HCMV) is a member of Herpesviridae family and is ubiquitous in the environment. After a primary asymptomatic infection, HCMV has a lifelong latency.[6] Infection with HCMV is typically harmless for children and adults but can have serious consequences for immunocompromised persons and developing fetuses.[7] Similar to other herpesviruses, HCMV has a unique proteinaceous layer between the virion envelope and capsid, named the tegument. During infection, the contents of the tegument layer are transported to the host cell, along with the capsid and the viral genome, where they promote the preliminary stages of virus replication. The tegument proteins also play vital roles in virion muster and this dual nature makes them attractive potential targets for antiviral therapies. Whereas our knowledge regarding tegument protein function during the initiation of infection has been the subject of intense study, their roles in gathering are much less well understood.[8]

Cytomegaloviru (CMV) have been implicated in the etiology of several human cancers; including cervical carcinoma,[9] adenocarcinomas of the prostate [10] and colon,[11] Kaposi's sarcoma,[12] and brain.[13] However, there is a lack of literature regarding the relationship between HCMV and NPC. HCMV was isolated in cell cultures derived from 2 of 11 NPC biopsy specimens from North African patients.[14] Since the relationship between EBV and NPC was previously reported in the same context, the aim of this study was to screen for CMV in tissue biopsies obtained from Sudanese patients with NPC.


 > Materials and Methods Top


In this study, 150 formalin fixed paraffin wax processed tissue samples of NPC were obtained from previously operated patients from different histopathology laboratories in Khartoum State, Sudan. All tissue samples were from those who had not yet given anti-cancer therapy. The sample size represents a full coverage.

DNA extraction

DNA was extracted from paraffin-embedded samples, by immersing tissue section in xylene to dissolve the paraffin from the tissue, and then rehydrated using a series of ethanol washes. Proteins and harmful enzymes such as nucleases were digested by proteinase K. Buffer containing denaturing agent (sodium dodecyl sulfate), was added to facilitate digestion.[15] Nucleic acids were purified from the tissue lysate using buffer-saturated phenol and high-speed centrifugation. Following phenol extractions, RNase A was added to eliminate contaminating RNA. Additional phenol extractions the following incubation with RNase A were used to remove any remaining enzyme. Sodium acetate and isopropanol were added to precipitate DNA, and high-speed centrifugation was used to pellet the DNA and facilitate isopropanol removal. Washing with 70% ethanol was performed to remove excess salts, followed by centrifugation to re-pellet the DNA.[16],[17] DNA was re-suspended in distilled water, quantified and stored at −20°C purified DNA was subsequently used in downstream applications of polymerase chain reaction.

Data analysis

Data analysis was done by using the Statistical Package for Social Sciences (SPSS version 16, Chicago, SPSS Inc.). Fisher exact test for statistical significance was used (P < 0.05 was considered significant).

Ethical consent

Before the study conducted the proposal of the study was ethically approved by ethical committee of the Sudan University of Science and Technology. Then the informed consent was agreed by the general managers of all histopathology laboratories in Khartoum State, Sudan.


 > Results Top


This study investigated tissue blocks obtained from 150 patients who were previously diagnosed with NPC, their ages ranging from 17 to 88 years with a mean age of 51 years. Males:females ratio was 1:00 to 1.83. Of the 150 NPC tissue specimens, HCMV was identified in 53/150 (35.3%) samples and could not be identified in 97/150 (64.7%). Of the 53 positive samples, 36/53 (68%) were found to harbor EBV. Out of the 53 samples infected with CMV, 33/97 (34%) among males and 20/53 (37.7%) were among females. The 95% confidence interval and the odd ratio for sex males/females were 0.851 (0.424–1.707), P < 0.389, as indicated in [Figure 1].
Figure 1: Description of proportions of positive human Cytomegalovirus in each age group

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As shown in [Table 1], the highest frequency of infection rates were seen among age group (>30 years) representing 13/53 (24.5%) followed by age range 31–45 and 46–60 years, constituting 12/53 (22.6%) and 10/53 (18.9%), in this order. However, when counting the percentage within entire groups, the greatest proportion of infection was found in age group 76+ years constituting 56% followed by <30 years, 31–45, 61–75, and 46–60 years, representing 43.3%, 36.4%, 27.8%, and 27%, respectively, as indicated in [Figure 2].
Table 1: Distribution of the study population by age and human Cytomegalovirus infection

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Figure 2: Description of the study population by sex and human Cytomegalovirus

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In regard to the residence and HCMV infection, the great majority of infections were identified among Western populations, representing 24/53 (45.3%) followed by South, Khartoum, Northern and Eastern, constituting 10/53 (18.8%), 8/53 (15%), 6/53 (11%), and 5/53(9%), respectively, as shown in [Table 2]. However, when counting the percentage within the entire residence, the greatest proportion of infection was also found in the West representing 43.6% followed by South (34.5%), North (33.3%), Khartoum (29.6%), and East (23.8%), as indicated in [Figure 3].
Table 2: Distribution of the study population by residence and human Cytomegalovirus infection

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Figure 3: Description of study population by residence and human Cytomegalovirus infection

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 > Discussion Top


Though HCMV is commonly regarded as nononcogenic virus, but HCMV infection has been connected to malignant diseases from different cancer entities.[18] Developing evidence proves that HCMV is repeatedly identified in tissue samples with very high prevalence in patients with cancers of different origin, comprising glioblastoma, neuroblastoma, medulloblastomas, colon, breast, prostate, mucoepidermoid, rhabdomyosarcoma, and salivary gland tumors.[19],[20],[21],[22],[23],[24] Due to its elevated prevalence in cancer, HCMV may play a substantial role in the founding of a number of cancer's forms.

In regard to the relationship between HCMV and NPC, localized nasopharyngeal HCMV infection has rarely been reported. However, HCMV infection of the nasopharynx has been previously reported. In a study of 201 infants with respiratory tract infection, HCMV was isolated in the nasopharyngeal aspirates from 10.9% of the patients. It was shown that HCMV viral load was not related to clinical respiratory symptoms or nasopharyngeal mass.[25] HCMV was identified in a case report of a man presented with a nasopharyngeal mass of 1 month's duration. Histology of the nasopharyngeal biopsy revealed several enlarged epithelial cells with characteristic HCMV cytopathic changes. An immunohistochemical study, using a monoclonal IgG antibody against an HCMV antigen, confirmed HCMV infection.[26] However, the percentage reported in the present study represents a considerable attention to the relationship between HCMV and NPC. To the best of our knowledge, this is the first report in this context.

In a recent study, the presence of HCMV proteins and nucleic acids was identified in 94% of sentinel lymph node metastases of breast cancer.[24] Cumulative evidence proposes that HCMV is associated with colorectal cancer (CRC). The viral nucleic acids specifically localized to the neoplastic mucosal epithelium of CRC, which usually predict a poor outcome in elderly patients. In the past decade, the concept of “oncomodulation” of HCMV in human cancers has been formulated. In CRC, changes in the tumor microenvironment are closely related to cancer behavior and prognosis, while the underlying mechanism driving these changes remains unclear. As HCMV affects multiple cellular functions, including signal pathways that regulate angiogenesis, apoptosis, cell invasiveness, and anti-cancer immunity, the virus potentially exerts oncomodulatory effects in the tumor microenvironment of CRC.[27]

The presence of HCMV proteins and nucleic acids at very high levels in primary and metastatic tumors may drive the progress of metastatic brain tumors; consequently, this virus may represent a potential therapeutic target in metastatic cancer.[28]

However, there is a possibility of the presence of other viruses, with more strong potentiality in causing NPC. In a recent study from Sudan, screened for the presence of EBV among Sudanese patients with NPC, EBV genes were detected in 61.3% tissue samples.[29] Another study screened for human papillomavirus (HPV) infections in head and neck squamous cell carcinomas (HNSCCs) using P16 immunostaining, HPV was identified in 20.7% of the cases of HNSCCs.[5]

Furthermore, the results of the present study require future onsite assessment of various environmental and other demographical measures.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet 2005;365:2041-54.  Back to cited text no. 1
[PUBMED]    
2.
Cui C, Liu L, Ma J, Liang S, Tian L, Tang L, et al. Trigeminal nerve palsy in nasopharyngeal carcinoma: Correlation between clinical findings and magnetic resonance imaging. Head Neck 2009;31:822-8.  Back to cited text no. 2
[PUBMED]    
3.
Lo K, Tsao S, Leung S, Choi P, Lee J, Huang D. Detailed deletion mapping on the short arm of chromosome-3 in nasopharyngeal carcinomas. Int J Oncol 1994;4:1359-64.  Back to cited text no. 3
[PUBMED]    
4.
Yu MC, Ho JH, Lai SH, Henderson BE. Cantonese-style salted fish as a cause of nasopharyngeal carcinoma: Report of a case-control study in Hong Kong. Cancer Res 1986;46:956-61.  Back to cited text no. 4
[PUBMED]    
5.
Ahmed HG, Mustafa SA, Warille E. Human papilloma virus attributable head and neck cancer in the sudan assessed by p16INK4A immunostaining. Asian Pac J Cancer Prev 2012;13:6083-6.  Back to cited text no. 5
[PUBMED]    
6.
de Jong MD, Galasso GJ, Gazzard B, Griffiths PD, Jabs DA, Kern ER, et al. Summary of the II international symposium on Cytomegalovirus. Antiviral Res 1998;39:141-62.  Back to cited text no. 6
[PUBMED]    
7.
Dollard SC, Keyserling H, Radford K, Amin MM, Stowell J, Winter J, et al. Cytomegalovirus viral and antibody correlates in young children. BMC Res Notes 2014;7:776.  Back to cited text no. 7
[PUBMED]    
8.
Smith RM, Kosuri S, Kerry JA. Role of human Cytomegalovirus tegument proteins in virion assembly. Viruses 2014;6:582-605.  Back to cited text no. 8
[PUBMED]    
9.
Huang E, Boldogh I, Mar E. Human cytomegaloviruses: Evidence for possible association with human cancer. In: Philips LA, editor. Viruses Associated with Human Cancer. New York: Marcel Dekker, Inc.; 1983. p. 161-93.  Back to cited text no. 9
    
10.
Boldogh I, Baskar JF, Mar EC, Huang ES. Human Cytomegalovirus and herpes simplex type 2 virus in normal and adenocarcinomatous prostate glands. J Natl Cancer Inst 1983;70:819-26.  Back to cited text no. 10
[PUBMED]    
11.
Huang ES, Roche JK. Cytomegalovirus D.N.A. and adenocarcinoma of the colon: Evidence for latent viral infection. Lancet 1978;1:957-60.  Back to cited text no. 11
    
12.
Boldogh I, Beth E, Huang ES, Kyalwazi SK, Giraldo G. Kaposi's sarcoma. IV. Detection of CMV DNA, CMV RNA and CMNA in tumor biopsies. Int J Cancer 1981;28:469-74.  Back to cited text no. 12
    
13.
Alibek K, Kakpenova A, Baiken Y. Role of infectious agents in the carcinogenesis of brain and head and neck cancers. Infect Agent Cancer 2013;8:7.  Back to cited text no. 13
[PUBMED]    
14.
Desgranges C, Seigneurin JM, Baccard M, Nejmi S. Cytomegalovirus isolations from cell cultures derived from Epstein-Barr virus-associated nasopharyngeal carcinoma. J Natl Cancer Inst 1983;71:39-43.  Back to cited text no. 14
[PUBMED]    
15.
Hilz H, Wiegers U, Adamietz P. Stimulation of proteinase K action by denaturing agents: Application to the isolation of nucleic acids and the degradation of 'masked' proteins. Eur J Biochem 1975;56:103-8.  Back to cited text no. 15
[PUBMED]    
16.
Sambrook J. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press; 2001.  Back to cited text no. 16
    
17.
Pikor LA, Enfield KS, Cameron H, Lam WL. DNA extraction from paraffin embedded material for genetic and epigenetic analyses. J Vis Exp 2011;49:e2763.  Back to cited text no. 17
    
18.
Michaelis M, Doerr HW, Cinatl J. The story of human Cytomegalovirus and cancer: Increasing evidence and open questions. Neoplasia 2009;11:1-9.  Back to cited text no. 18
[PUBMED]    
19.
Soroceanu L, Cobbs CS. Is HCMV a tumor promoter? Virus Res 2011;157:193-203.  Back to cited text no. 19
[PUBMED]    
20.
Melnick M, Sedghizadeh PP, Allen CM, Jaskoll T. Human Cytomegalovirus and mucoepidermoid carcinoma of salivary glands: Cell-specific localization of active viral and oncogenic signalling proteins is confirmatory of a causal relationship. Exp Mol Pathol 2012;92:118-25.  Back to cited text no. 20
[PUBMED]    
21.
Baryawno N, Rahbar A, Wolmer-Solberg N, Taher C, Odeberg J, Darabi A, et al. Detection of human Cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest 2011;121:4043-55.  Back to cited text no. 21
[PUBMED]    
22.
Price RL, Bingmer K, Harkins L, Iwenofu OH, Kwon CH, Cook C, et al. Cytomegalovirus infection leads to pleomorphic rhabdomyosarcomas in Trp53/- mice. Cancer Res 2012;72:5669-74.  Back to cited text no. 22
[PUBMED]    
23.
Taher C, de Boniface J, Mohammad AA, Religa P, Hartman J, Yaiw KC, et al. High prevalence of human Cytomegalovirus proteins and nucleic acids in primary breast cancer and metastatic sentinel lymph nodes. PLoS One 2013;8:e56795.  Back to cited text no. 23
[PUBMED]    
24.
Wolmer-Solberg N, Baryawno N, Rahbar A, Fuchs D, Odeberg J, Taher C, et al. Frequent detection of human Cytomegalovirus in neuroblastoma: A novel therapeutic target? Int J Cancer 2013;133:2351-61.  Back to cited text no. 24
[PUBMED]    
25.
Wejse C, Birkebaek NH, Nielsen LP, Andersen HM. Respiratory tract infections in Cytomegalovirus-excreting and nonexcreting infants. Pediatr Infect Dis J 2001;20:256-9.  Back to cited text no. 25
[PUBMED]    
26.
Chan BW, Woo JK, Liew CT. Cytomegalovirus infection of the nasopharynx. J Clin Pathol 2002;55:970-2.  Back to cited text no. 26
[PUBMED]    
27.
Chen HP, Chan YJ. The oncomodulatory role of human Cytomegalovirus in colorectal cancer: Implications for clinical trials. Front Oncol 2014;4:314.  Back to cited text no. 27
[PUBMED]    
28.
Taher C, Frisk G, Fuentes S, Religa P, Costa H, Assinger A, et al. High prevalence of human Cytomegalovirus in brain metastases of patients with primary breast and colorectal cancers. Transl Oncol 2014;7:732-40.  Back to cited text no. 28
[PUBMED]    
29.
Ahmed HG, Suliman RS, El Aziz MS, Alshammari FD. Molecular screening for Epstein Barr virus (EBV) among Sudanese patients with nasopharyngeal carcinoma (NPC). Infect Agent Cancer 2015;10:6.  Back to cited text no. 29
[PUBMED]    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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