Epstein-Barr Virus Causes Nasopharyngeal Cancer

In addition to its original linkages with Burkitt's lymphoma and infectious mononucleosis, Epstein-Barr virus is now believed to be the cause of nasopharyngeal carcinoma, T-cell and natural killer (NK) cell lymphomas, and Hodgkin's disease, and is also implicated in gastric carcinomas and lymphoepithelioma-like lung cancer. As usual, the anti-smokers ignore the role of this virus in order to falsely blame smoking and passive smoking.

EBV has been declared a Class I human carcinogen by the IARC. (Epstein Barr Virus and Kaposi's Sarcoma Herpesvirus/Human Herpesvirus 8. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans). IARC Monograph 70. Lyon: International Agency for Research on Cancer; 1997.)

"5.5 Evaluation. There is sufficient evidence for the carcinogenicity of EBV in the causation of Burkitt's lymphoma, sinonasal angiocentric T-cell lymphoma, immunosuppression-related lymphoma, Hodgkin's disease and nasopharyngeal carcinoma."

"EBV is carcinogenic to humans (Group I)."

IARC Monograph 70, Epstein-Barr Virus, summary (1997) / IARC (pdf, 10 pp)


Epstein-Barr Virus and Cancer. MP Thompson, R Kurzrock. Clinical Cancer Research 2004 Feb;10(3):803-821. Review. "The EBV genomes present in the epithelial cells of the nasopharynx are of clonal origin, and EBV is absent from surrounding tissues and invading T lymphocytes. EBV has also been detected in in situ nasopharyngeal carcinoma, a precursor of undifferentiated nasopharyngeal carcinoma. These findings suggest that EBV infection occurs before neoplasia and is necessary for the progression of the malignant phenotype."

Thompson & Kurzrock / Clin Cancer Res 2004 full article

Other reviews

Epstein-Barr virus, infectious mononucleosis, Burkitt's lymphoma and nasopharyngeal carcinoma. G Klein. Israel J Med Sci 1977 Jul;13(7):716-724. "The timing and extent of seroconversion are strongly related to socioeconomic status. In low socioeconomic groups, infection occurs during early childhood, as a rule. It is not accompanied by any recognized disease, and the route of transmission is unknown. Only a minority of children become infected in high socioeconomic groups where a later infection, during the teens, predominates."

Klein - Israel J Med Sci 1977 full article / UCSF (pdf, 9 pp)

Epstein-Barr virus infections and their association with human malignancies: some key questions. BE Griffin, SA Xue. Ann Med 1998 Jun;30(3):249-259. "Many questions partly addressed here remain with regard to this virus, two critical ones relating to the mechanisms by which viral gene products excape T-cell recognition -- relevant from the fact that gene expression is not tightly restricted to nonimmunogenic functions in tumours -- and whether EBV can invoke cell growth in a manner not requiring its continued presence. The latter seems a plausible hypothesis and is of particular importance with regard to identifying and understanding pathologies associated with EBV, as viral transcription transactivators may on initial infection permanently perturb cell regulation."

Griffin - Ann Med 1998 abstract / PubMed

Epstein-Barr virus: the first human tumor virus and its role in cancer. JS Pagano. Proc Assoc Am Physicians 1999 Nov-Dec;111(6):573-580. "The relation of the virus to the malignancies varies from primary etiologic agent to necessary or contributory co-factor... Most of the malignancies occur after years of viral dormancy and are accompanied or triggered by viral reactivation, in contrast to infectious mononucleosis, which results from primary infection with EBV."

Pagano - Proc Assoc Am Physicians 1999 abstract / PubMed

Epstein-Barr virus-associated diseases in humans. K Kawa. Int J Hematol 2000 Feb;71(2):108-117. Review.

Kawa - Int J Hematol 2000 abstract / PubMed

Haematological associations of Epstein-Barr virus infection. M Okano. Baillieres Best Pract Res Clin Haematol 2000 Jun;13(2):199-214.

Okano - Baillieres Best Pract Res Clin Haematol 2000 abstract / PubMed

Tonsillar memory B cells, latently infected with Epstein-Barr virus, express the restricted pattern of latent genes previously found only in Epstein-Barr virus-associated tumors. GJ Babcock, DA Thorley-Lawson. Proc Natl Acad Sci 2000 Oct 24;97(22): 12250-12255.

Babcock / PNAS 2000 full article

The role of epstein-barr virus in neoplastic transformation. H Knecht, C Berger, S Rothenberger, BF Odermatt, P Brousset. Oncology 2001;60(4):289-302. Review.

Knecht - Oncology 2001 abstract / PubMed

Epstein-Barr virus (EBV) and human disease: facts, opinions and problems. BE Griffin. Mutat Res 2000 Apr;462(2-3):395-405. Review. "We also consider tumours where the viral association is reportedly of low frequency, and offer explanations for these data, including the possibility of the loss of the viral genome once malignancy has been initiated. If this phenomenon occurs as a frequent secondary event, EBV could be an even greater health risk than presently believed."

Griffin - Mutat Res 2001 abstract / PubMed

EBV in Nasopharyngeal Carcinoma

Antibodies to Epstein-Barr virus in nasopharyngeal carcinoma, other head and neck neoplasms, and control groups. W Henle, G Henle, HC Ho, P Burtin, Y Cachin, P Clifford, A de Schryver, G de-The, V Diehl, G Klein. J Natl Cancer Inst 1970 Jan;44(1):225-231. "Of 235 East African and Chinese patients who were classified as cases of nasopharyngeal carcinoma (NPC), 84% had high anti-EBV titers," and the histopathology "seemed irrelevant." Antibody levels increased according to stage.

Henle - J Natl Cancer Inst 1970 full article / UCSF (pdf, 7 pp)

Antibodies to Epstein-Barr virus in nasopharyngeal cancer and other neoplastic conditions. SD Kottaridis, M Dafnou, S Besbeas, J Garas. J Natl Cancer Inst 1977 Jul;59(1):89-91. "The data reaffirmed the association of EBV with NPC."

Kottaridis - J Natl Cancer Inst 1977 abstract / PubMed

Relationship between the Epstein-Barr virus and undifferentiated nasopharyngeal carcinoma: correlated nucleic acid hybridization and histopathological examination. M Andersson-Anvret, N Forsby, G Klein, W Henle. Int J Cancer 1977 Oct 15;20(4):486-494. "a correlated histopathological and nucleic acid hybridization study was performed on 51 undifferentiated NPC, 4 NPC with some signs of squamous differentiation, 7 nasophayngeal tumors of other histological types and 14 head and neck carcinomas located outside the nasopharynx. All 51 undifferentiated NPCs contained significant numbers of EBV-genome copies per cell. Two of the somewhat differentiated NPCs were also EBV-DNA-positive, whereas 2 were negative. Of the 7 other nasopharyngeal tumors, 1 was EBV-DNA-positive. Histological examination, however, showed that this was a typical Burkitt lymphoma. The other 6 tumors were all EBV-DNA-negative lymphoproliferative malignancies. All 14 had head and neck carcinomas located outside the nasopharynx were EBV-DNA-negative. The sera of undifferentiated NPC patients had elevated antibody titers against the EBV-determined antigens, the EA (D) componet in particular. These findings confirm that there is a regular association between EBV-DNA and undifferentiated NPC."

Andersson-Anvret - Int J Cancer 1977 abstract / PubMed

Human nasopharyngeal carcinomas positive for Epstein-Barr virus DNA in North America. R Glaser, M Nonoyama, RT Szymanowski, W Graham. J Natl Cancer Inst 1980 Jun;64(6):1317-1319. "Nasopharyngeal carcinomas (NPC) from 2 black patients and 1 Caucasian patient were positive for Epstein-Barr virus (EBV) DNA. Of the tumors, 2 were lymphoepitheliomas (undifferentiated NPC) and 1 was a moderately differentiated NPC. All 3 patients had high IgG titers against EBV early antigen and high IgG and IgA titers against virus capsid antigen (VCA). In one patient, the levels of anti-VCA IgA were different than those of anti-VCA IgG over the course of the disease. Our data support the association of EBV and NPC in North America."

Glaser - J Natl Cancer Inst 1980 full article / UCSF (pdf, 5 pp)

Nasopharyngeal cancer in Alaskan Eskimos, Indians, and Aleuts: A review of cases and study of Epstein-Barr virus, HLA, and environmental risk factors. A Lanier, T Bender, M Talbot, S Wilmeth, C Tschopp, W Henle, G Henle, D Ritter, P Terasaki. Cancer 1980 Nov 1;46(9):2100-2106. In 25 males and 6 females, "Antibodies to Epstein-Barr virus were higher in NPC patients than in patients with other tumors or matched controls... In response to a questionnaire, NPC patients more often reported use of salt fish in the childhood diet, smoking of cigarettes, and exposure to noxious inhalants than did controls, but the differences were not statistically significant."

Lanier - Cancer 1980 abstract / PubMed
Lanier - Cancer 1980 full article / UCSF (pdf, 7 pp)

Anti-EBV serologic tests for nasopharyngeal carcinoma. HB Neel 3rd, GR Pearson, LH Welland, WF Taylor, HH Goepfert, BZ Pilch, AP Lanier, AT Huang, VJ Hyams, PH Levine, G Henle, W Henle. Laryngoscope 1980 Dec;90(12):1981-1990. In 63 American patients, "The level of antibody titers to EBV-associated antigens was correlated with nasopharyngeal carcinoma. The anti-EBV profile of elevated antibody titers directed against viral capsid antigen and early antigen was seen in undifferentiated and nonkeratinizing tumors but usually not in squamous cell tumors."

Neel - Laryngoscope 1980 abstract / PubMed

The reliability of IgA antibody to Epstein-Barr virus (EBV) capsid antigen as a test for the diagnosis of nasopharyngeal carcinoma (NPC). PH Levine, GR Pearson, M Armstrong, Z Bengali, J Berenberg, J Easton, H Goepfert, G Henle, W Henle, D Heffner, A Huang, VJ Hyams, A Lanier, HB Neel, B Pilch, N Pointek, W Taylor, H Terebolo, L Weiland. Cancer Detect Prev 1981;4(1-4):307-312. "The prospective study showed a relationship between IgA antibody titers and histopathology but not disease stage. IgA antibody titers were elevated more frequently in patients with nonkeratinizing or poorly differentiated types of NPC than for the well-differentiated squamous cell carcinomas. While IgA antibodies to EBV VCA appear to be of value in the early detection and diagnosis of NPC, it is possible that additional serologic tests for immunity to EBV, such as IgG antibody to VCA or early antigen (EA), will improve even further the clinical value of EBV serology in the management of NPC."

Levine - Cancer Detect Prev 1981 abstract / PubMed

Association of Epstein-Barr virus with nasopharyngeal carcinoma in Alaskan native patients: serum antibodies and tissue EBNA and DNA. AP Lanier, GW Bornkamm, W Henle, G Henle, TR Bender, ML Talbot, PH Dohan. Int J Cancer 1981 Sep 15;28(3):301-305. "EBV DNA and EBNA results were in agreement in 29 of 31 tissue specimens tested by the two methods." 10/11 NPC biopsies were EBV+, as were 2 atypical epithelium biopsies, which were 1 lymphoepithelial lesion of the parotid gland and 1 undifferentiated salivary gland carcinoma.

Lanier - Int J Cancer 1981 abstract / PubMed

Application of Epstein-Barr virus (EBV) serology to the diagnosis of North American nasopharyngeal carcinoma. GR Pearson, LH Weiland, HB Neel 3rd, W Taylor, J Earle, SE Mulroney, H Goepfert, A Lanier, ML Talvot, B Pilch, M Goodman, A Huang, PH Levine, V Hyams, E Moran, G Henle, W Henle. Cancer 1983 Jan 15;51(2):260-268. "The results suggest that certain anti-EBV antibodies are of potential value for the diagnosis of undifferentiated types of NPC but not for the well-differentiated cancer. The IgA anti-VCA antibody response is the most specific for this disease and of the greatest diagnostic value when used alone or in combination with the anti-EA test. These tests have also been used successfully for the detection of occult NPC. These results indicate that these tests can be useful aids to the clinician for the diagnosis of certain histopathologic types of this disease."

Pearson - Cancer 1983 abstract / PubMed

Application of Epstein-Barr virus serology to the diagnosis and staging of North American patients with nasopharyngeal carcinoma. HB Neel 3rd, GR Pearson, LH Weiland, WF Taylor, HH Goepfert, BZ Pilch, M Goodman, AP Lanier, AT Huang, VJ Hyams, PH Levine, G Henle, W Henle. Otolaryngol Head Neck Surg 1983 Jun;91(3):255-262. "From 1978 to 1981, 151 patients with nasopharyngeal carcinoma (NPC) were enrolled in a prospective, collaborative study of North American patients, most of them white. Thirty-seven had World Health Organization (WHO) type 1 tumors, and 114 had WHO types 2 and 3 tumors. The anti-Epstein-Barr virus (EBV) profile of elevated antibody titers directed against viral capsid antigen and early antigen was seen in 85% of the patients with WHO types 2 and 3 tumors but in only 16% of the patients with WHO type 1 tumors."

Neel - Otolaryngol Head Neck Surg 1983 abstract / PubMed

Epstein-Barr virus antibody titers in cancer of the head and neck. DJ Callaghan, BR Connor, M Strauss. Arch Otolaryngol 1983 Dec;109(12):781-784. "Pretreatment serum samples from 39 white American patients with epidermoid cancer of various sites of the head and neck, including the nasopharynx, were studied for both IgA and IgG antibodies to the Epstein-Barr virus (EBV)-specific antigens. Of the various serological assays, IgG anti-viral capsid antigen (VCA) was least specific and was present frequently at high titers in both the groups with nasopharyngeal carcinoma (NPC) and groups with other cancers (OC). The geometric mean titer (GMT) of IgA anti-VCA was significantly elevated in patients with NPC compared with the groups with OC. The incidence of this virologic parameter was high in the laryngeal and stage III and IV oral cavity groups of epidermoid cancer, and the GMTs were significantly greater than the control group. Finally, the GMTs of all the antibodies to the EBV-associated antigens were significantly elevated in patients with NPC who had regional metastases compared with those who had local disease with cranial nerve involvement."

Callaghan - Arch Otolaryngol 1983 abstract / PubMed

Evaluation of antibodies to Epstein-Barr virus in Italian patients with nasopharyngeal carcinoma. R Cevenini, M Donati, U Caliceti, A Moroni, I Tamba, F Rumpianesi. J Infect 1986 Mar;12(2):127-131. Confiming the association of EBV with NPC. "An association of Epstein-Barr virus (EBV) with nasopharyngeal carcinoma (NPC) has been established serologically in Italian patients. The finding of IgA antibodies to EBV-capsid antigen (VCA) and to early antigen (EA) showed a high degree of correlation for patients with NPC, thereby confirming previous reports. In addition, when considered together, IgA anti-VCA and IgG anti-EA antibody titres appeared to distinguish NPC-patients from those in control populations. Poorly differentiated and undifferentiated carcinomas with lymphoid cellular infiltrations showed the highest frequency of association with positive EBV serological tests."

Cevenini - J Infect 1986 abstract / PubMed

Epstein-Barr virus seroepidemiology in China. Y Zeng, GH Pi, H Deng, JM Zhang, PC Wang, H Wolf, G De The. AIDS Res 1986 Dec;2 Suppl 1:S7-S15. In a prospective study of EBV positivity and nasopharyngeal cancer in 20,726 people, 1,138 had IgA VCA antibody. 18 NPC cases were found in these, and 21 more during five years of follow-up. "The detection rate of NPC from IgA VCA antibody-positive persons is 38-374 times the incidence rate of NPC in the general population of the same age group... No NPC patients were found in the original antibody negative group" [emphasis added].

Zeng - AIDS Res 1986 abstract / PubMed

The differentiated form of nasopharyngeal carcinoma contains Epstein-Barr virus DNA. N Raab-Traub, K Flynn, G Pearson, A Huang, P Levine, A Lanier, J Pagano. Int J Cancer 1987 Jan 15;39(1):25-29. "24 undifferentiated and 4 partially differentiated specimens generally contained a relatively high number of EBV genome equivalents, while the 5 well-differentiated NPC all contained detectable EBV, but at low copy number... These findings indicate that all histologic subsets of NPC contain EBV DNA" [emphasis added].

Raab-Traub - Int J Cancer 1987 abstract / PubMed

Serological and immunohistochemical assessment of Epstein-Barr virus infection in Sicilian patients with suspected nasopharyngeal carcinoma. P Ammatuna, G de The, R Speciale, F Sammartano, S Arista, G Zerillo. Microbiologica 1988 Apr;11(2):89-94. 8/9 NPC patients had high EBV antibody levels; and 1/4 without NPC but with high antibody levels later developed NPC.

Ammatuna - Microbiologica 1988 abstract / PubMed

Expression of Epstein-Barr virus-encoded proteins in nasopharyngeal carcinoma. R Fahraeus, HL Fu, I Ernberg, J Finke, M Rowe, G Klein, K Falk, E Nilsson, M Yadav, P Busson, et al. Int J Cancer 1988 Sep 15;42(3):329-338. "All 16 cases of clinically diagnosed and histologically confirmed NPCs from North Africa contained EBV DNA and expressed EBNA-1." 29/31 from China contained EBV DNA, and tumors from Malaysia and East Africa showed a similar pattern of expression.

Fahraeus - Int J Cancer 1988 abstract / PubMed

Multiple risk factors of nasopharyngeal carcinoma: Epstein-Barr virus, malarial infection, cigarette smoking and familial tendency. C-J Chen, K-Y Liang, Y-S Chang, Y-F Wang, T Hsieh, M-W Hsu, J-Y Chen, M-Y Liu. Anticancer Res 1990 Mar;10(2B):547-553. The magic of multivariate analysis produces confounding again: "The older the age, the more striking the dose-response relation between cigarette smoking and NPC," where the causal factor EBV and the non-causal smoking are linked socioeconomically, and cohort effects produce further confusion, which contrary to pretenses, cannot be separated by statistical means.

Chen - Anticancer Res 1990 abstract / PubMed

Detection of Epstein-Barr virus DNA in formalin-fixed pariffin-embedded tissue of nasopharyngeal carcinoma using polymerase chain reaction and in situ hybridization. I Akao, Y Sato, K Mukai, H Uhara, S Furuya, T Hoshikawa, Y Shimosato, I Takeyama. Laryngoscope 1991 Mar;101(3):279-283. In Japanese patients, "Detection rates of Epstein-Barr virus in various types of nasopharyngeal carcinoma according to the World Health Organization classification were as follows: 10 of 10 undifferentiated carcinomas, 8 of 13 nonkeratinizing carcinomas, and 5 of 7 keratinizing carcinomas."

Akao - Laryngoscope 1991 abstract / PubMed

Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. L Brooks, Q Y Yao, A B Rickinson and L S Young. J Virol 1992 May;66(5):2689-2697. "All four transplantable NPC cell lines studied and 17 of 18 fresh snap-frozen NPC biopsy specimens expressed an EBNA1 mRNA with a BamHI Q/U/K splice structure exactly like that recently identified in group I Burkitt's lymphoma (BL) cell lines and shown to be driven from a novel viral promoter, Fp."

Brooks et al / J Virol 1992 abstract
Brooks et al / J Virol 1992 full article (pdf, 9pp)

Herbal medicine use, Epstein-Barr virus, and risk of nasopharyngeal carcinoma. A Hildesheim, S West, E DeVeyra, MF De Guzman, A Jurado, C Jones, J Imai, Y Hinuma. Cancer Res 1992 Jun 1;52(11):3048-3051. 104 cases, 205 controls in The Philippines. "Subjects strongly positive for anti-EBV antibodies (Epstein-Barr nuclear antigen [EBNA]) (titers greater than or equal to 1:80) were at a 21-fold excess risk of disease (95% confidence interval, 8.4, 51.8)... Exposure to herbal medicines among subjects testing negative/weakly positive for anti-EBNA antibodies was not associated with an elevation in risk (relative risk, 0.6), strong positivity to anti-EBNA antibodies in the absence of herbal medicine use was associated with a significant 16-fold excess risk of disease, and exposure to herbal medicines among subjects testing strongly positive for anti-EBNA antibodies was associated with a significant 49-fold excess risk of NPC when cases were compared to controls."

Hildesheim - Cancer Res 1992 abstract / PubMed

Nasopharyngeal carcinoma: histopathological types and association with Epstein-Barr virus. U Hording, HW Nielsen, H Albeck, S Daugaard. Eur J Cancer B Oral Oncol 1993 Apr;29B(2):137-139. 23/23 nonkeratinizing and undifferentiated, and 2/14 keratinizing NPCs were positive for EBV genomic sequences.

Hording - Eur J Cancer B Oral Oncol 1993 abstract / PubMed

Epstein-Barr virus infection, salted fish and nasopharyngeal carcinoma. A case-control study in southern China. X Zheng, L Yan, B Nilsson, G Eklund, B Drettner B. Acta Oncol 1994;33(8):867-872. 205 cases in south China. "Multivariate analyses showed that IgA/VCA was the most important predictor of NPC, and salted fish the second most important. These results suggest that EBV has a strong effect on the development of NPC. The exclusion of EBV and genetic factors in earlier epidemiological studies may have resulted in an overestimation of salted fish as important etiological factor causing NPC."

Zheng - Acta Oncol 1994 abstract / PubMed

[The value of polymerase chain reaction on Epstein-Barr virus subtypes in the differentiation of benign and malignant nasopharyngeal biopsies]. N Sun, X Chen. Zhonghua Er Bi Yan Hou Ke Za Zhi 1995;30(4):213-215. A proportion of patients with chronic nasopharyngitis are also positive for EBV by PCR.

Sun - Zhonghua Er Bi Yan Hou Ke Za Zhi 1995 abstract / PubMed

Undifferentiated, nonkeratinizing, and squamous cell carcinoma of the nasopharynx. Variants of Epstein-Barr virus-infected neoplasia. R Pathmanathan, U Prasad, G Chandrika, R Sadler, K Flynn, N Raab-Traub. Am J Pathol 1995 Jun;146(6):1355-1367. "Nasopharyngeal carcinoma (NPC) samples of distinct histological types, including squamous cell carcinoma (WHO type 1), nonkeratinizing carcinoma (WHO type 2), and undifferentiated carcinoma (WHO type 3), were analyzed for Epstein-Barr virus (EBV) infection and gene expression by using in situ and biochemical techniques. The EBV-encoded RNAs (EBER) were detected in situ in most tumor cells of all three WHO types of NPC. In foci of squamous differentiation and keratinization within less differentiated NPC and throughout the expanse of well differentiated squamous cell carcinoma, EBER expression was less abundant. Latent membrane protein, an EBV-encoded membrane protein, was detected in 72% (36/50) of all NPC and 67% (6/9) of the cases of squamous cell carcinoma. The EBV genomes were present as clonal episomal forms, without detectable linear viral DNA, in all cases of squamous cell carcinoma analyzed. Polymerase chain reaction amplification of cDNA detected EBV transcription for Epstein-Barr nuclear antigen 1, latent membrane proteins 1 and 2, and BamHI A in all samples, indicating that all forms of NPC express the same EBV genes. These results reveal that EBER expression is significantly decreased in areas with squamous differentiation and confirm that all types of NPC, regardless of histological type or differentiation contain clonal episomal EBV genomes, express specific EBV genes and are a clonal expansion of EBV-infected cells."

Pathmanathan - Am J Pathol 1995 full article / PubMed Central

Detection of Epstein-Barr virus genome in sinonasal undifferentiated carcinoma by use of in situ hybridization. O Gallo, S Di Lollo, P Graziani, E Gallina, G Baroni. Otolaryngol Head Neck Surg 1995 Jun;112(6):659-664. Epstein-Barr virus DNA was detected in 38% (5 of 13) of nose and paranasal sinus carcinomas.

Gallo - Otolaryngol Head Neck Surg 1995 abstract / PubMed

Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. R Pathmanathan, U Prasad, R Sadler, K Flynn, N Raab-Traub. N Engl J Med 1995 Sep 14;333(11):693-698. "Evidence of EBV infection was detected in all 11 tissue samples with dysplasia or carcinoma in situ. EBERs were identified in all eight samples tested, and LMP-1 was detected in all six of the tested samples. Six of the seven samples tested for the EBV termini contained clonal EBV DNA. Transcription of the latent EBV gene products, EBV nuclear antigen 1, LMP-1, LMP-2A, and the BamHI-A fragment, was detected in most of the samples. Viral proteins characteristic of lytic lesions were not detected. CONCLUSIONS. Preinvasive lesions of the nasopharynx are infected with EBV. The EBV DNA is clonal, indicating that the lesions represent a focal cellular growth that arose from a single EBV-infected cell and that EBV infection is an early, possibly initiating event in the development of nasopharyngeal carcinoma. Preinvasive lesions contain EBV RNAs that are characteristic of latent infection but not the viral proteins that are characteristic of lytic infection. The detection of the EBV-transforming gene, LMP-1, in all the neoplastic cells suggests that its expression is essential for preinvasive epithelial proliferations associated with nasopharyngeal carcinoma."

Pathmanathan et al. NEJM 1995 abstract / PubMed
Pathmanathan et al. / NEJM 1995 full article

Epstein–Barr virus — Increasing evidence of a link to carcinoma. (Editorial re Pathmanathan.) E Kieff. N Engl J Med 1995 Sep 14;333(11):724-726.

Kieff / NEJM 1995 full article

Nasopharyngeal carcinoma: Epstein-Barr virus significance. SD Kottaridis, E Panotopoulos, I Diamantis, I Goula, J Danilidis, G Fountzilas. Anticancer Res 1996 Mar;16(2):785-789. In 31 NPCs, there was association with EBV; "no correlation between smoking and NPC was found."

Kottaridis - Anticancer Res 1996 abstract / PubMed

Use of bacterially expressed GST/EBNA-1 fusion proteins for detection of antibodies in sera from patients with nasopharyngeal carcinoma and healthy donors. MR Chen, JF Yang, TY Hsu, MY Liu, JY Chen, CS Yang. Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi 1996 May;29(2):65-79. All 38 NPCs were IgG positive for EBNA-1 in sera, versus only 2.6% of 38 healthy controls.

Chen - Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi 1996 abstract / PubMed

Enhanced malignant progression of nasopharyngeal carcinoma cells mediated by the expression of Epstein-Barr nuclear antigen 1 in vivo. LF Sheu, A Chen, CL Meng, KC Ho, WH Lee, FJ Leu, CF Chao. J Pathol 1996 Nov;180(3):243-248. "EBNA 1 caused HONE-1 cells to grow in a less differentiated pattern and to progress more rapidly, as well as increasing their tumourigenicity and metastatic capability."

Sheu - J Pathol 1996 abstract / PubMed

Epstein-Barr viral DNA in serum of patients with nasopharyngeal carcinoma. A Mutirangura, W Pornthanakasem, A Theambooniers, V Sriuranpong, P Lertsanguansinchi, S Yenrudi, N Voravud, P Supiyaphun, Y Poovorawan. Clin Cancer Res 1998 Mar;4(3):665-669. 13/42 NPC samples were EBV DNA-positive in sera, vs. 0/82 controls.

Mutirangura - Clin Cancer Res 1998 abstract / PubMed

Comparative analysis of Epstein-Barr virus (EBV) detection by nested-PCR and non-isotopic in situ hybridization in nasopharyngeal carcinoma (NPC). F Vera-Sempere, J Burgos, MS Botella, C Morera. Clin Chim Acta 1998 Mar 23;271(2):119-132. In 54/55 cases with adequate quality DNA samples, "EBV-DNA was detected in 100% of cases using a nested-PCR, supporting the previous view that all histological types of NPC are in reality variants of EBV-infected neoplasia" [emphasis added].

Vera-Sempere - Clin Chim Acta 1998 abstract / PubMed

Epstein-Barr virus detection in nasopharyngeal tissues of patients with suspected nasopharyngeal carcinoma. ST Tsai, YT Jin, RB Mann, RF Ambinder. Cancer 1998 Apr 15;82(8):1449-1453. 98.1% EBV+ by ISH. "In specimens from 107 patients with NPC, EBV was detected by PCR in 97 cases (90.7%) and by EBER in situ hybridization in 105 cases (98.1%). In specimens from 61 patients without neoplasia, EBV was detected by PCR in 7 cases (11.5%) and by EBER in situ hybridization in 0 cases."

Tsai - Cancer 1998 abstract / PubMed

Antibody against the Epstein-Barr virus BHRF1 protein, a homologue of Bcl-2, in patients with nasopharyngeal carcinoma. MY Liu, YY Shih, SP Chou, TS Sheen, CS Yang, JY Chen. J Med Virol 1998 Nov;56(3):179-185. "The demonstration of anti-BHRF1 antibody in most NPC sera strongly supports the hypothesis that the EBV BHRF1 protein is expressed in most NPC patients and its specific antibody can be a useful marker for the diagnosis of NPC."

Liu - J Med Virol 1998 abstract / PubMed

Human papillomavirus may be common within nasopharyngeal carcinoma of Caucasian Americans: investigation of Epstein-Barr virus and human papillomavirus in eastern and western nasopharyngeal carcinoma using ligation-dependent polymerase chain reaction. R Punwaney, MS Brandwein, DY Zhang, ML Urken, R Cheng, CS Park, HB Li, X Li. Head Neck 1999 Jan;21(1):21-29. 30 patients (6 Caucasian Americans, 1 Chinese American, 14 and 9 patients from Korea and China). "Human papillomavirus appears to be uncommonly (17%) associated with NPC in patients from the Far East and was detected more often (50%) in NPC from American Caucasian patients." 5/6 Caucasian Americans were EBV-positive.

Punwaney - Head Neck 1999 abstract / PubMed

Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal cancer. YMD Lo, LYS Chan, K-W Lo, S-F Leung, J Zhang, ATC Chan, JCK Lee, NM Hjelm, PJ Johnson, DP Huang. Cancer Res 1999 Mar 15;59(6):1188-1191. 96% of 57 NPC patients and 7% of 43 control relatives were EBV+; disappearance of viral DNA corresponded with complete tumor regression.

Lo / Cancer Res 1999 full article

Detection of human papilloma virus and Epstein-Barr virus DNA in nasopharyngeal carcinoma by polymerase chain reaction. YC Tung, KH Lin, PY Chu, CC Hsu, WR Kuo. Kao Hsiang I Hsueh Ko Hsueh Tsa Chih 1999 May;15(5):256-262. In 88 NPC tissue samples, "HPV and EBV DNA were detected in 51% and in 83% of the specimens, respectively. Coexistence of EBV and HPV in NPC was found in 42% of the samples. The "high risk" types including HPV-16 and HPV-18 accounted for 67% of 45 HPV positive samples. Furthermore, 80% of HPV-16 or HPV-18 positive samples also contained EBV DNA."

Tung - Kao Hsiang I Hsueh Ko Hsueh Tsa Chih 1999 abstract / PubMed

Quantitative and temporal correlation between circulating cell-free Epstein-Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. TM Lo, LY Chan, SF Leung, KW Lo, J Zhang, JC Lee, NM Hjelm, PJ Johnson, DP Huang. Cancer Res 1999 Nov 1;59(21):5452-5455. Among 17 patients, "Continuous low or undetectable levels of serum EBV DNA were observed in the patients who remained in remission," versus a median of 32,350 copies/ml in relapsed patients.

Lo / Cancer Res 1999 full article

Epstein-Barr virus strain characterisation in South African patients with nasopharyngeal carcinomas. E Janse van Rensburg, WF van Heerden, BA Robson, TJ Swart, S Engelbrecht. Anticancer Res 2000 May;20(3B):1953-1957. "EBV could be detected in 82% (31/38) of the tumours."

Janse van Rensburg - Anticancer Res 2000 abstract / PubMed

Association of Epstein-Barr virus (EBV) with nasopharyngeal carcinoma (NPC). SH Shah, IN Soomro, S Haroon, T Moatter. J Pak Med Assoc 2000 Jun;50(6):182-183. 6/17 were EBV+, marker not specified.

Shah - J Pak Med Assoc 2000 abstract / PubMed

Epstein-Barr virus infection of sinonasal lymphoepithelial carcinoma in Guangzhou. Y Zong, K Liu, B Zhong, G Chen, W Wu. Chin Med J (Engl) 2001 Feb;114(2):132-136. "This tumor is also consistently associated with EBV infection like NPC" (20/20).

Zong - Chin Med J 2001 abstract / PubMed
Zong / Chin Med J 2001 full article

Detection of Epstein-Barr virus DNA in the peripheral-blood cells of patients with nasopharyngeal carcinoma: relationship to distant metastasis and survival. JC Lin, KY Chen, WY Wang, JS Jan, WM Liang, CS Tsai, YH Wei. J Clin Oncol 2001 May 15;19(10):2607-2615; and: Distant metastases and poor prognoses indicated by Epstein-Barr virus DNA 1 in nasopharyngeal cancer. By Veronica Rose, Doctor's Guide News 2001 May 21.

Lin - J Clin Oncol 2001 abstract / PubMed
Lin - J Clin Oncol 2001 Full Article
Lin / Doctor's Guide News 2001

Expression of Epstein-Barr virus-encoded RNA and biological markers in Italian nasopharyngeal carcinomas. E Gabusi, C Lattes, M Fiorentino, A D'Errico, WF Grigioni. J Exp Clin Cancer Res 2001 Sep;20(3):371-376. 23/26 (88%) of cases were positive for either EBER1, or bcl-2 protein or mRNA. "This study of NPC in Italy confirms the importance of EBV and bcl-2 in Western cases."

Gabusi - J Exp Clin Cancer Res 2001 abstract / PubMed

Occupational exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal carcinoma. A Hildesheim, M Dosemeci, CC Chan, CJ Chen, YJ Cheng, MM Hsu, IH Chen, BF Mittl, B Sun, PH Levine, JY Chen, LA Brinton, CS Yang. Cancer Epidemiol Biomarkers Prevent 2001 Nov;10(11):1145-1153. 98.6% of 375 cases versus 29.6% of 325 controls were positive for antibodies to EBV markers associated with NPC, resulting in a 170-fold [one hundred and seventy times!!!] geater risk. Their claim that "Other factors associated with NPC in our study and considered as potential confounders in our analyses include 25 years of cigarette smoking (RR = 1.7; 95% CI = 1.1–2.9)" is bogus, because puny little RRs of 1.7 are easily generated by confounding by great big RRs of 170 - not vice-versa. Among other things, stratification can't undo the effect of earlier age at EBV infection. Also, as an occupational study it's ridiculous (and all too typical), because there were no actual measurements of exposure to formaldehyde, just a guess by an industrial hygienist based on job descriptions. But this was the only study involving EBV that was cited by the IARC in its declaration that formaldehyde is a human carcinogen!

Hildesheim / Cancer Epidemiol Biomarkers Prevent 2001 full article

Serological markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. YC Cien, JY Chen, MY Liu, HI Yang, MM Hsu, CJ Chen, CS Yang. NEJM 2001 Dec 27;345(26):1877-1882. 22 cases. In a prospective study, the OR for NPC with both markers of EBV was 32.8 (95% CI 7.3-147.2; P=0.003); and with one marker, 4.0 (1.6 to 10.2; P=0.003).

Chien - NEJM 2001 abstract / PubMed
Chien - NEJM 2001 Full Article (with free registration)

Assessing the risk of nasopharyngeal carcinoma on the basis of EBV antibody spectrum. WM Cheng, KH Chan, HL Chen, RX Luo, SP Ng, W Luk, BJ Zheng, MF Ji, JS Liang, JS Sham, DK Wang, YS Zong, MH Ng. Int J Cancer 2002 Feb 1;97(4):489-492. "The risk of the cancer was markedly reduced with odds ratios of 0.009 for 59% of those who had low level of all 3 antibodies. The risk was increased as antibody spectrum broadens and the risk was the highest with an odds ratio of 138 for 0.4% of those who had high levels of all 3 antibodies."

Cheng - Int J Cancer 2002 abstract / PubMed

Sinonasal undifferentiated carcinoma and nasopharyngeal-type undifferentiated carcinoma: two clinically, biologically, and histopathically distinct entities. YM Jeng, MT Sung, CL Fang, HY Huang, TL Mao, W Cheng, CH Hsiao. Am J Surg Pathol 2002 Mar;26(3):371-376. All 36 SNUC tumors were negative for EBER-1 by in situ hybridization, while all 13 primary sinonasal nasopharyngeal-type undifferentiated carcinomas were positive for EBER-1 by in situ hybridization.

Jeng - Am J Surg Pathol 2002 abstract / PubMed

Improved accuracy of detection of nasopharyngeal carcinoma by combined application of circulating Epstein-Barr virus DNA and anti-Epstein-Barr viral capsid antigen IgA antibody. SF Leung, JS Tam, AT Chan, B Zee, LY Chan, DP Huang, A Van Hasselt, PJ Johnson, YM Lo. Clin Chem 2004 Feb;50(2):339-345. "The sensitivities of EBV DNA and IgA-VCA for diagnosis of NPC were 95% (95% confidence interval, 91-98%) and 81% (73-87%), respectively. The combined marker panel had an overall sensitivity (positive result by either marker) of 99%. The concentrations of both markers showed dependence on cancer stage. The specificities of EBV DNA and IgA-VCA were 98% (96-99%) and 96% (91-98%), respectively. Among 36 healthy family members with false-positive IgA-VCA results, three-fourths had undetectable EBV DNA, whereas the others had increased EBV DNA concentrations that were significantly lower than in NPC patients."

Leung / Clin Chem 2004 full article

Prevalence and relevance of EBV latency in nasopharyngeal carcinoma in Israel. G Bar-Sela, A Kuten, I Minkov, E Gov-Ari, O Ben-Izhak. J Clin Pathol 2004 Mar;57(3):290-293. 3/5 patients with squamous cell carcinoma were EBV positive and 37/40 non-keratinising and undifferentiated carcinoma cases were positive.

Bar-Sela - J Clin Pathol 2004 abstract / PubMed

Molecular characterization of Epstein-Barr virus and oncoprotein expression in nasopharyngeal carcinoma in Korea. YK Jeon, BY Lee, JE Kim, SS Lee, CW Kim. Head Neck 2004 Jul;26(7):573-583. "EBER was detected in 55 of 57 cases (96%) of nonkeratinizing carcinoma (NKC) and undifferentiated carcinoma, but in only four of nine cases (44%) of squamous cell carcinoma (SCC)."

Jeon - Head Neck 2004 abstract / PubMed

Evaluation of risk factors for nasopharyngeal carcinoma in high-risk nasopharyngeal carcinoma families in Taiwan. XR Yang, S Diehl, R Pfeiffer, CJ Chen, WL Hsu, M Dosemeci, YJ Cheng, B Sun, AM Goldstein, A Hildesheim; Chinese and American Genetic Epidemiology of NPC Study Team. Cancer Epidemiol Biomarkers Prev 2005 Apr;14(4):900-905. "Interestingly, cigarette smoking, especially with longer duration (20 years), seemed inversely related to NPC risk. The patterns observed were similar in analyses restricted to all cases and 501 controls seropositive for antibodies against EBV, except for the attenuated effect of RSA allele." In this study population, ORs for >20 years of cigarette smoking in analysis of all subjects (502 cases and 1942 controls): 0.66 (95% confidence intervals, 0.45-0.96). "Similar results were obtained from analyses using ever/never smoking status, smoking intensity, and pack-years of smoking (data not shown). In addition, in contrast to an earlier report that age at start of smoking was inversely associated with the risk of NPC (32), our data showed no such association (ORage 18-21, 0.92; 95% CI, 0.66-1.28; ORage >22, 1.03; 95% CI, 0.75-1.42). The inversely related effect of cigarette smoking was even stronger in familial case to population control comparisons, suggesting that familial cases smoked less compared with either control groups."

Yang / Cancer Epidemiol Biomarkers Prev 2005 full article

Detection of EBV and HPV in nasopharyngeal carcinoma by in situ hybridization. N Mirzamani, P Salehian, M Farhadi, EA Tehran. Exp Mol Pathol 2006 Dec;81(3):231-234. "EBER-ISH was positive in 19 (95%) of NPCs evaluated and in one metastases from cervical primary, included in this series. Two of 20 NPC (10%) contained HPV 6/11 sequences and two of 20 NPC (10%) contained HPV 16/18 sequences, and combined EBV and HPV infection was detected in 3 of the 20 (15%) patients."

Mirzamani - Exp Mol Pathol 2006 abstract / PubMed

Expression of Epstein-Barr-virus-encoded small nuclear RNA in nasopharyngeal carcinomas of Aegean Turkish patients. Y Ertan, M Hekimgil, S Karaarslan, S Soydan. Virchows Arch 2008 Apr;452(4):411-414. "Seventy-three of 84 cases were EBER positive. All of 62 cases (100.0%) with undifferentiated carcinoma, 8 of 16 (50.0%) with differentiated nonkeratinizing carcinoma, and three of six (50.0%) with keratinizing squamous cell carcinoma were EBV positive."

Ertan - Virchows Arch 2008 abstract / PubMed

Human papilloma virus detection in neoplastic and non-neoplastic nasopharyngeal tissues in Taiwan. CC Huang, JR Hsiao, MW Yang, YH Wu, KF Hsu, Y Chang, CW Chen, ST Tsai, HP Wei, YT Jin. J Clin Pathol 2011 Jul;64(7):571-577. 43 primary NPCs, 40 controls. "[O]ncogenic HPVs were detected equally in WHO-II/III NPCs (31%, 13/42) and nasopharyngeal controls (35%, 14/40). Tumour high-risk HPV status did not correlate with the prognosis of patients with NPC. In the high-risk HPV in situ hybridisation cohort, 14 (88%) of the 16 oncogenic HPV-positive WHO-II/III NPCs showed a unique cytoplasmic/perinuclear staining pattern, which is distinct from the typical dot/punctate nuclear staining pattern indicating HPV genome integration. In addition, oncogenic HPVs were not always retained in NPC cells during the process of metastasis."

Huang - J Clin Pathol 2011 abstract / PubMed

The incidence of Epstein-Barr virus in nasopharyngeal carcinoma of Jordanian patients. I Matalka, M Al Hamad, M Al-Hussaini, FQ Alzoubi. Eur Arch Otorhinolaryngol 2012 Jan;269(1):229-234. 92.3% of 39 cases were positive for EBERs.

Matalka - Otorhinolaryngol 2012 abstract / PubMed

Oncogenic human papillomavirus-associated nasopharyngeal carcinoma: an observational study of correlation with ethnicity, histological subtype and outcome in a UK population. M Robinson, YE Suh, V Paleri, D Devlin, B Ayaz, L Pertl, S Thavaraj. Infect Agent Cancer 2013 Aug 12;8(1):30. 67 patients with clinically validated NPC. "Eleven cases (11/67, 16.4%) showed concurrent over-expression of p16 and evidence of high-risk HPV DNA by in-situ hybridisation; the majority were HPV16 positive." None were coinfected with EBV.

Robinson - Infect Agent Cancer 2013 abstract / PubMed

Nonendemic HPV-Positive Nasopharyngeal Carcinoma: Association With Poor Prognosis. MH Stenmark, JB McHugh, M Schipper, HM Walline, C Komarck, FY Feng, FP Worden, GT Wolf, DB Chepeha, ME Prince, CR Bradford, SK Mukherji, A Eisbruch, TE Carey. Int J Radiat Oncol Biol Phys 2014 Mar 1;88(3):580-588. "Of 61 evaluable tumors, 26 (43%) were EBV-positive/HPV-negative, 18 (30%) were HPV-positive/EBV-negative, and 17 (28%) were EBV/HPV-negative. EBV and HPV infection was mutually exclusive. HPV positivity was significantly correlated with World Health Organization grade 2 tumors, older age, and smoking (all P<.001)."

Stenmark - Int J Radiat Oncol Biol Phys 2014 abstract / PubMed

Human papillomavirus 16 detected in nasopharyngeal carcinomas in Caucasian Americans but not in endemic Southern Chinese patients. Z Lin, B Khong, S Kwok, H Cao, RB West, QT Le, CS Kong. Head Neck 2014 May;36(5):709-714. 86 southern Chinese and 108 patients from Stanford. "No HPV(+) cases were detected in the Chinese cohort. In the Stanford cohort, 5/11 EBV(-) cases harbored HPV16, 10/10 occurred in Caucasians, and 8/11 were smokers. Patients with EBV(-) NPC also showed a trend towards worse survival."

Lin - Head Neck 2014 abstract / PubMed

EBV Mechanisms in Nasopharyngeal Carcinoma

Epstein-Barr Virus and methylation of the p16 gene

Expression of Epstein-Barr virus genes and of lymphocyte activation molecules in undifferentiated nasopharyngeal carcinomas. G Niedobitek, LS Young, CK Sam, L Brooks, U Prasad and AB Rickinson. Am J Pathol 1992 Apr;140(4):879-887. In 18 undifferentiated NPCs positive for EBV, almost all cases expressed the CDw70 antigen, which in normal tissues is present only in activated lymphoid blasts.

Niedobitek et al. / Am J Pathol 1992 abstract

EBNA-1: a protein pivotal to latent infection by Epstein-Barr virus. ER Leight, B Sugden. Rev Med Virol 2000 Mar;10(2):83-100.

Leight - Rev Med Virol 2000 abstract / PubMed

High level expression of deltaN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)? T Crook, JM Nicholls, L Brooks, J O'Nions, MJ Allday. Oncogene 2000 Jul 13;19(30):3439-3444.

Crook - Oncogene 2000 abstract / PubMed

Expression of BARF1 gene encoded by Epstein-Barr virus in nasopharyngeal carcinoma biopsies. G Decaussin, F Sbih-Lammali, M de Turenne-Tessier, A Bouguermouh, T Ooka. Cancer Res 2000 Oct 1;60(19):5584-5588. Possible role of BARF1 in malignant transformation.

Decaussin - Cancer Res 2000 abstract / PubMed
Decaussin - Cancer Res 2000 Full Article

Ethnic differences in the expression of Epstein-Barr virus latent membrane protein-1 mutations in nasopharyngeal carcinoma. M D'Addario, P Chauvin. Mutat Res 2000 Dec 20;457(1-2):69-78. "While 68% of the total group expressed EBV-antigens, only 56% of Caucasians but 86% of Inuit expressed this viral protein. Over 67% of Inuit NPC tissue contained the characteristic 30 bp deletion that was observed in only 20% of Caucasians and 33% of Chinese samples."

D'Addario - Mutat Res 2000 abstract / PubMed

Loss of heterozygosity and its correlation with clinical outcome and Epstein-Barr virus infection in nasopharyngeal carcinoma. JY Shao, XM Huang, XJ Yu, LX Huang, QL Wu, JC Xia, HY Wang, QS Feng, ZF Ren, I Ernberg, LF Hu, YX Zeng. Anticancer Res 2001 Jul-Aug;21(4B):3021-3029. "High frequency LOH (> or = 60%) was observed on 12 chromosome arms including 1p, 2p, 2q, 3p, 3q, 5q, 9p. 9q, 11q, 13q, 14q and 17q, with the highest LOH frequency of 91% on 3p. Seventy-three loci presented LOH frequency > or = 30%; most of these loci clustered on 1p36 p34, 2p25-p24, 3p14-p21, 3p24-p26, 5q11-q14, 5q31-q33, 9p21-p23, 9q33-q34, 11q23-q25, 13q12 q14, 13q31-q33, 14q13-q11, 14q32 and 19q13. On 1p36-p34, 2p25-p24, 5q13-q11, 5q31-q33 and 19q13 are reported for the first time."

Shao - Anticancer Res 2001 abstract / PubMed

Prevention and inhibition of nasopharyngeal carcinoma growth by antiviral phosphonated nucleoside analogs. S Murono, N Raab-Traub, JS Pagano. Cancer Res 2001 Nov 1;61(21):7875-7877. Lead sentence: "Nasopharyngeal cancer is universally associated with EBV infection." This mouse study suggests that anti-viral drugs could prevent and/or treat it.

Murono - Cancer Res 2001 abstract / PubMed
Murono - Cancer Res 2001 Full Article

Epstein-Barr virus in the pathogenesis of NPC. N Raab-Traub. Semin Cancer Biol 2002 Dec;12(6):431-441. Review. "Epstein-Barr virus (EBV) is consistently detected in nasopharyngeal carcinoma (NPC) from regions of high and low incidence. EBV DNA within the tumor is homogeneous with regard to the number of terminal repeats. The detection of a single form of viral DNA suggests that the tumors are clonal proliferations of a single cell that was initially infected with EBV. Specific EBV genes are consistently expressed within the NPC tumors and in early, dysplastic lesions. The viral proteins, latent membrane protein 1 and 2, have profound effects on cellular gene expression and cellular growth, resulting in the highly invasive, malignant growth of NPC tumors. In addition to potential genetic changes, the establishment of a latent, transforming infection in epithelial cells is likely to be a major contributing factor to the development of this tumor."

Raab-Traub - Semin Cancer Biol 2002 abstract / PubMed

Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. N Khan, A Hislop, N Gudgeon, M Cobbold, R Khanna, L Nayak, AB Rickinson, PA Moss. J Immunol 2004;173(12):7481-7489. "Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status. The functional activity of the herpesvirus-specific immune response decreases in elderly donors, although the characteristic phenotypes of CMV- and EBV-specific memory populations are retained. This demonstrates that aging is associated with a marked accumulation of CMV-specific CD8 T cells together with a decrease in immediate effector function. Moreover, infection with CMV can reduce prevailing levels of immunity to EBV, another persistent virus. These results suggest that carriage of CMV may be detrimental to the immunocompetent host by suppressing heterologous virus-specific immunity during aging."

Khan / J Immunol 2004 full article
CMV Impairs Immunity

The Epstein-Barr Virus-Encoded LMP2A and LMP2B Proteins Promote Epithelial Cell Spreading and Motility. MD Allen, LS Young, CW Dawson. J Virology 2005 Feb;79(3):1789-1802.

Allen / J Virology 2005 full article

Frequent hypermethylation of RASSF1A and TSLC1, and high viral load of Epstein-Barr Virus DNA in nasopharyngeal carcinoma and matched tumor-adjacent tissues. L Zhou, W Jiang, C Ren, Z Yin, X Feng, W Liu, Q Tao, K Yao K. Neoplasia 2005 Sep;7(9):809-815. Hypermethylated RASSF1A was frequently detected in nasopharyngeal carcinoma tissues (82%) and matched tumor-adjacent tissues outside 0.5 cm (75%), but less frequently in tissues outside 1.0 cm (46%).

Zhou - Neoplasia 2005 abstract / PubMed

Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells. C Man, J Rosa, LT Lee, VH Lee, BK Chow, KW Lo, S Doxsey, ZG Wu, YL Kwong, DY Jin, AL Cheung, SW Tsao. Oncogene 2007 May 10;26(21):3069-3080. "[W]e observed that LMP1 expression in human epithelial cells could induce aberrant mitotic spindles, disorganized interphase microtubules and aneuploidy. LMP1 expression could also suppress microtubule dynamics as exemplified by tracking movements of the growing tips of microtubules in live cells by transfecting EGFP-tagged EB1 into cells. The aberrant mitotic spindles and interphase microtubule organization induced by LMP1 could be rescued by transfecting RASSF1A expression plasmid into cells."

Man - Oncogene 2007 abstract / PubMed

Epstein-Barr Virus Latent Nuclear Antigens Can Induce Metastasis in a Nude Mouse Model. R Kaul, M Murakami, T Choudhuri, ES Robertson. J Virol 2007 Oct;81(19):10352-10361. "The EBV critical latent antigens EBNA1 and EBNA3C interact with Nm23-H1, a known suppressor of cell migration and tumor metastasis. This interaction is critical for the regulation of downstream cellular genes involved in tumorigenesis and cell migration. The significance of these interactions was determined in nude mice using cancer cells expressing both EBV antigens and Nm23-H1. The EBV antigens promoted the growth of transformed cells in vivo, but their expression was less critical during the later stage of tumor development. The expression of Nm23-H1 affected the growth of cancer cells and suppressed their metastatic potential. This effect was effectively rescued by the expression of both EBV antigens. Interestingly, the prometastatic potential of EBNA3C was greater than that of EBNA1, which triggered a dramatic immune response, as indicated by increased spleen size and development of ascites in the mice. These studies now bridge the expression of the EBV antigens with tumorigenesis and metastasis and widen the range of potential targets for development of therapies for EBV-associated malignancies."

Kaul / J Virol 2007 full article

Epstein Barr Virus Nuclear Antigen 3C interacts with and enhances the stability of the c-Myc oncoprotein. BG Bajaj, M Murakami, Q Cai, SC Verma, K Lan, ES Robertson. J Virol 2008 Apr;82(8):4082-4090. "In this report, we show that EBNA3C residues 130-190 previously shown to bind to the SCF(Skp2) complex can also strongly associate with the c-Myc oncoprotein. Additionally, the interaction of EBNA3C with c-Myc was mapped to the region of c-Myc that includes the highly conserved Skp2 binding domain. Skp2 has been shown to regulate c-Myc stability and has also been shown to function as a co-activator of transcription for c-Myc target genes. We now show that the EBV latent oncoprotein EBNA3C can stabilize c-Myc and that recruitment of both c-Myc and its cofactor Skp2 to c-Myc dependent promoters can enhance c-Myc dependent transcription. This same region of EBNA3C also recruits and modulates the activity of pRb and p27, both major regulators of the mammalian cell cycle."

Bajaj / J Virol 2008 full article

Epstein-Barr Virus Immediate Early Protein Zta Co-Opts Mitochondrial Single Stranded DNA Binding Protein To Promote Viral And Inhibit Mitochondrial DNA Replication. A Wiedmer, P Wang, J Zhou, AJ Rennekamp, V Tiranti, M Zeviani, PM Lieberman. J Virol 2008 May;82(9):4647-4655. "Epstein-Barr virus (EBV) lytic replication is initiated by the immediate-early protein Zta... Mitochondrial DNA synthesis and genome copy number were reduced by Zta-induced EBV lytic replication." "Lytic infection is observed at high rates in patients with oral hairy leukoplakia and EBV-positive gastric carcinoma. Elevated levels of EBV lytic antigens are a prognostic risk factor for nasopharyngeal carcinoma in regions of endemicity."

Wiedmer / J Virol 2008 full article

Meta-analysis of nasopharyngeal carcinoma microarray data explores mechanism of EBV-regulated neoplastic transformation. X Chen, S Liang, W Zheng, Z Liao, T Shang, W Ma. BMC Genomics 2008 Jul 7;9:322. "Our analysis suggests that NPC transformation depends on timely regulation of DEK, CDK inhibitor(s), p53, RB and several transcriptional cascades, interconnected by E2F, AP-1, NF-kappaB, STAT3 among others during latent and lytic cycles."

Chen / BMC Genomics 2008 full article
Chen - BMC Genomics 2008 full article / PubMed Central

Epstein-Barr virus latent membrane protein 1 represses DNA repair through the PI3K/Akt/FOXO3a pathway in human epithelial cells. YR Chen, MT Liu, YT Chang, CC Wu, CY Hu, JY Chen. J Virol 2008 Aug;82(16):8124-8137. "In the present study, we demonstrate that the PI3K/Akt pathway is required for LMP1-mediated repression of DNA repair. Through the LMP1/PI3K/Akt pathway, FOXO3a, which can induce DNA repair, is inactivated because of phosphorylation and relocalization. Expression of a constitutively active FOXO3a mutant can rescue LMP1-mediated repression of DNA repair. Furthermore, LMP1 can decrease the expression of DNA damage-binding protein 1 (DDB1), which functions in nucleotide excision repair, through the PI3K/Akt/FOXO3a pathway."

Chen / J Virol 2008 full article

Latent membrane protein 1 of Epstein-Barr virus activates the hTERT promoter and enhances telomerase activity in B lymphocytes. L Terrin, J Dal Col, E Rampazzo, P Zancai, M Pedrotti, G Ammirabile, S Bergamin, S Rizzo, R Dolcetti, A De Rossi. J Virol 2008 Oct;82(20):10175-10187. "In the present study, we provide evidence indicating that, in B lymphocytes, LMP1 directly promotes the activation of telomerase by acting at the transcriptional level on the hTERT promoter. These effects are mediated by engagement of the NF-κB, MAPK, and ERK1/2 pathways." LMP1 transactivates the hTERT promoter in both epithelial and B cells.

Terrin - J Virol 2008 full article / PubMed Central

Epstein-Barr Nuclear Antigen 1 Contributes to Nasopharyngeal Carcinoma through Disruption of PML Nuclear Bodies. N Sivachandran, F Sarkari, L Frappier. PLoS Pathog 2008 Oct;4(10):e1000170. "EBNA1 is required for the replication and stable persistence of EBV episomes in proliferating cells and is the only EBV protein that is expressed in all EBV-associated tumors." "We show that the viral EBNA1 protein, previously known to be required to maintain the EBV episomes, also causes the disruption of the cellular PML (promyelocytic leukemia) nuclear bodies (or ND10s). This disruption occurs both in the context of a native latent infection and when exogenously expressed in EBV-negative NPC cells and involves loss of the PML proteins. We also show that EBNA1 is partially localized to PML nuclear bodies in NPC cells and interacts with a specific PML isoform. PML disruption by EBNA1 requires binding to the cellular ubiquitin specific protease, USP7 or HAUSP, but is independent of p53. We further observed that p53 activation, DNA repair and apoptosis, all of which depend on PML nuclear bodies, were impaired by EBNA1 expression and that cells expressing EBNA1 were more likely to survive after induction of DNA damage." "While initially identified as a gene whose rearrangement leads to promyelocytic leukemia, it has since been found that loss of the PML protein is associated with cancer development for a variety of human tumors. In addition, mice lacking PML develop normally but their cells are more prone to malignant transformation."

Sivachandran / PLoS Pathog 2008 full article

Epstein-Barr virus LF2: An antagonist to type I interferon. L Wu, E Fossum, CH Joo, K Lee, YC Shin, E Johannsen, LM Hutt-Fletcher, J Hass, JU Jung. J Virol 2009 Jan;83(2):1140-1146. "Upon viral infection, the major defense mounted by the host immune system is activation of the interferon (IFN)-mediated antiviral pathway, which is mediated by IFN regulatory factors (IRFs). In order to complete their life cycle, viruses must modulate host IFN-mediated immune responses. Despite its association with significant human health problems, activities of Epstein-Barr virus (EBV), a human tumor-inducing herpesvirus, to evade host IFN-mediated innate immunity have not been well characterized. To search for EBV genes that block IFN signal transduction, we carried out a screening of EBV open reading frames for their abilities to block IFN-/β-mediated luciferase expression upon Sendai virus infection. This screening demonstrates that EBV LF2 tegument protein specifically interacts with the central inhibitory association domain of IRF7, and this interaction leads to inhibition of the dimerization of IRF7, which suppresses IFN- production and IFN-mediated immunity. This demonstrates a novel immune evasion mechanism of EBV LF2 in blocking cellular IRF7-mediated innate immunity."

Wu / J Virol 2009 abstract

Degradation of Phosphorylated p53 by Viral Protein-ECS E3 Ligase Complex. Y Sato, T Kamura, N Shirata, T Murata, A Kudoh, S Iwahori, S Nishiyama, T Tsurumi. PLoS Pathog 2009 Jul. "The Epstein-Barr virus (EBV) lytic program induces phosphorylation of p53, which prevents interaction with MDM2. Here, we show that induction of EBV lytic program leads to degradation of p53 via an ubiquitin-proteasome pathway independent of MDM2... Intringuingly, C-terminal phosphorylation of p53 resulting from activated DNA damage response by viral lytic replication enhances its binding to BZLF1 protein."

Sato / PLoS Pathog 2009 full article

Synergism of BARF1 with Ras induces malignant transformation in primary primate epithelial cells and human nasopharyngeal epithelial cells. R Jiang, G Cabras, W Sheng, Y Zeng, T Ooka. Neoplasia 2009 Sep;11(9):964-973. "Here, we have shown that overexpression of H-Ras gene transformed BARF1-immortalized PATAS cells into malignant cell line. Furthermore, we found that cooperation of BARF1 with H-Ras and SV40 T antigens was sufficient to transform nonmalignant human nasopharyngeal epithelial NP69 cells when serially introduced BARF1 and H-Ras into the SV40 T antigens-immortalized NP69 cells. Taken together, these results demonstrated that the cooperation of BARF1 with Ras suffices to transform primary primate epithelial cell PATAS. Similarly, BARF1 together with H-Ras and SV40 T can transform human epithelial cell NP69, thereby indicating that BARF1 could be involved in the NPC pathogenesis in combination with additional genetic changes."

Jiang - Neoplasia 2009 full article / PubMed Central

Toll-like Receptor Agonists Synergistically Increase Proliferation and Activation of B Cells by Epstein-Barr Virus. S Iskra, M Kalla, HJ Delecluse, W Hammerschmidt, A Moosmann. J Virol 2010 Apr;84(7):3612-3623. "CpG DNA alone activated only memory B cells, but CpG DNA enhanced EBV-mediated transformation both of memory and naive B cells. Ligands for TLR2 or TLR7/8, or whole bacteria, had a weaker but still superadditive effect on B cell transformation. Additionally, CpG DNA facilitated the release of transforming virus by established EBV-infected lymphoblastoid cell lines. These results suggest that the proliferation of EBV-infected B cells and their capability to interact with immune effector cells may be directly influenced by components of bacteria or other microbes present at the site of infection."

Iskra - J Virol 2010 abstract / PubMed

Epstein-Barr Virus-Encoded LMP2A Induces an Epithelial–Mesenchymal Transition and Increases the Number of Side Population Stem-like Cancer Cells in Nasopharyngeal Carcinoma. Q-L Kong, L-J Hu, J-Y Cao, Y-J Huang, L-H Xu, Y Liang, D Xiong, S Guan, B-H Guo, H-Q Mai, Q-Y Chen, X Zhang, M-Z Li, J-Y Shao, C-N Qian, Y-F Xia, L-B Song, Y-X Zeng, M-S Zeng. PLoS Pathog 2010 Jun 3;6(6):e1000940. "Our results suggest that LMP2A supports tumor initiation and recurrence of the infected nasopharyngeal epithelial cells. For the first time we report a virus protein that functions in the initiation and progression of cancer by inducing the cancer stem-like cells."

Kong / PLoS Pathog 2010 full article

Allelic imbalance and abnormal expression of FHIT in endemic nasopharyngeal carcinoma: association with clinicopathological features. YF Deng, DN Zhou, YD Lu. Eur Arch Otorhinolaryngol 2010 Dec;267(12):1933-1941. "[L]oss of heterozygosity (LOH) and microsatellite instability (MSI), at FHIT locus in 41 cases of NPC by microsatellite analysis and FHIT gene status in 30 cases of NPC by nested reverse transcriptase-polymerase chain reaction and DNA sequencing. The frequencies of LOH and MSI at FHIT locus in NPC were 70.7% (29/41) and 36.6% (15/41), respectively. Thirteen of thirty (43.3%) NPCs exhibited aberrant FHIT transcripts. LOH and abnormal FHIT expression were correlated with advanced clinical stage and higher titers of immunoglobulin (Ig) A against Epstein-Barr virus capsid antigen (EBVCA-IgA) (p < 0.05). Abnormal FHIT expression was also correlated with tumor recurrence (p < 0.05). MSI was correlated with early clinical stage and higher titers of EBVCA-IgA (p < 0.05)."

Deng - Eur Arch Otorhinolaryngol 2010 abstract / PubMed

Specific infiltration of langerin-positive dendritic cells in EBV-infected tonsil, Hodgkin lymphoma and nasopharyngeal carcinoma. PH Braz-Silva, S Vitale, C Butori, N Guevara, J Santini, M Magalhes, P Hofman, A Doglio. Int J Cancer 2011 May 1;128(10):2501-2508. "We report here the existence of a novel subset of langerin (CD207)-positive, immature dendritic cells (DCs) (CD83(neg)) abundantly infiltrating Epstein Barr virus (EBV)-infected areas in tonsil, Hodgkin lymphoma and nasopharyngeal carcinoma. These CD207(+) DCs differ from conventional epidermal Langerhans cells in their lack of CD1a and CCR6 and their unusual tissue localization. CD207(+) DC infiltration strongly correlates with EBV infection because it was neither detected in EBV negative specimens nor in tissues infected with other human viruses. These immature DCs might represent good candidates for induction of the EBV-specific immune response."

Braz-Silva - Int J Cancer 2011 abstract / PubMed

Genetic risk markers for nasopharyngeal carcinoma in Portugal: tumor necrosis factor alpha -308G >A polymorphism. H Sousa, E Breda, AM Santos, R Catarino, D Pinto, R Medeiros. DNA Cell Biol 2011 Feb;30(2):99-103. 123 patients with nasopharyngeal carcinoma, 627 healthy subjects. "-308AA genotype is associated with increased risk for the development of NPC (odds ratio = 2.46; 95% confidence interval, 0.98-6.17; p = 0.047); moreover, this effect was stronger in undifferentiated types, which are virtually 100% caused by the Epstein-Barr virus (odds ratio = 2.75; 95% confidence interval, 1.09-6.90; p = 0.025)."

Sousa - DNA Cell Biol 2011 abstract / PubMed

Epstein-Barr Virus Downregulates MicroRNA-203 through the Oncoprotein Latent Membrane Protein 1: a Contribution to Increased Tumor Incidence in Epithelial Cells. H Yu, J Lu, L Zuo, Q Yan, Z Yu, X Li, J Huang, L Zhao, H Tang, Z Luo, Q Liao, Z Zeng, J Zhang, G Li. J Virol 2012 Mar;86(6):3088-3099. "miR-203 was downregulated substantially in epithelial cells and NPC tissues that were latently infected with EBV. Downregulation of miR-203 also occurred during the early stage of EBV infection. Furthermore, the viral oncoprotein, latent membrane protein 1 (LMP1), was responsible for downregulation of miR-203... Ectopic expression of miR-203 inhibited EBV-induced S phase entry and transformation in vivo."

Yu - J Virol 2012 abstract / PubMed

BZLF1 governs CpG-methylated chromatin of Epstein-Barr Virus reversing epigenetic repression. A Woellmer, JM Arteaga-Salas, W Hammerschmidt. PLoS Pathog 2012 Sep;8(9):e1002902. "BZLF1 is the viral switch gene that induces the lytic phase of EBV's life cycle. We show here that this viral transcription factor erases static, repressive chromatin marks reversing epigenetic silencing. DNA methylation is preserved but no hindrance to lytic gene activation because BZLF1 directly binds to methylated viral DNA and overcomes heavily repressed chromatin without the need for active DNA demethylation. DNA demethylation has been thought to be a prerequisite for gene transcription but this virus falsifies this hypothesis and provides a new model for epigenetic gene regulation."

Woellmer - PLoS Pathog 2012 full article / PubMed CentralWoellmer / PLoS Pathog 2012 full article

Epstein-barr virus zta upregulates matrix metalloproteinases 3 and 9 that synergistically promote cell invasion in vitro. YY Lan, TH Yeh, WH Lin, SY Wu, HC Lai, FH Chang, K Takada, Y Chang. PLoS One 2013;8(2):e56121. "Ectopic Zta expression in EBV-negative cells increased both mRNA and protein production of MMP3. Endogenous Zta also contributed to induction of MMP3 expression, migration and invasion of EBV-infected cells... Zta-promoted cell migration required MMP3 but not MMP9. On the other hand, both MMP3 and MMP9 were essential for Zta-induced cell invasion, and co-expression of the two MMPs synergistically increased cell invasiveness."

Lan - PLoS One 2013 full article / PubMed Central
Lan / PLoS One 2013 full article

Human Leukocyte Antigens and Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma: Old Associations Offer New Clues into the Role of Immunity in Infection-Associated Cancers. WH Su, A Hildesheim, YS Chang. Front Oncol 2013 Dec 9;3:299. Review. "Of note, we report that MHC associations for EBV-associated cancers (NPC, EBV+ Hodgkin lymphoma) are driven by HLA class I genes. In contrast, MHC associations for other viral-associated cancers (cervical cancer, hepatocellular carcinoma) or other hematopoetic cancers (EBV- Hodgkin lymphoma, leukemia, non-Hodgkin lymphomas) are driven by HLA class II genes, and those for other solid tumors with less clear links to infections (lung, testicular, prostate cancers) are driven by non-HLA genes in the MHC region." The association between HLA genes and NPC has been confirmed in over 100 candidate-gene-based association studies. "More specifically, studies have reproducibly reported associations with NPC for the following HLA class I alleles: HLA-A*0207 (risk allele in LD with HLA-B*4601), HLA-A*1101 (protective allele in LD with HLA-B*13), and HLA-B*5801 (risk allele in LD with HLA-A*3303). Linkage analyses also suggested that HLA-A and HLA-B genes are associated with the development of NPC. Other HLA genes, including HLA-C and HLA class II genes, showed less consistent findings across studies."

Su - Front Oncol 2013 full article / PubMed Central
Su / Front Oncol 2013 full article

STAT3 interrupts ATR-Chk1 signaling to allow oncovirus-mediated cell proliferation. S Koganti, J Hui-Yuen, S McAllister, B Gardner, F Grasser, U Palendira, SG Tangye, AF Freeman, S Bhaduri-McIntosh. Proc Natl Acad Sci USA 2014 Apr 1;111(13):4946-4951. "EBV infection is rapidly followed by activation and increased expression of STAT3, which mediates relaxation of the intra-S phase cell-cycle checkpoint; this facilitates viral oncogene-driven cell proliferation. We now show that replication stress-associated DNA damage, which results from EBV infection, is detected by DDR. However, signaling downstream of ATR is impaired by STAT3, leading to relaxation of the intra-S phase checkpoint. We find that STAT3 interrupts ATR-to-Chk1 signaling by promoting loss of Claspin, a protein that assists ATR to phosphorylate Chk1. This loss of Claspin which ultimately facilitates cell proliferation is mediated by caspase 7, a protein that typically promotes cell death."

Koganti - Proc Natl Acad Sci USA 2014 abstract / PubMed

Oncogenic effects of WNT5A in Epstein-Barr virus‑associated nasopharyngeal carcinoma. LF Yap, M Ahmad, MM Zabidi, TL Chu, SJ Chai, HM Lee, PV Lim, W Wei, C Dawson, SH Teo, AS Khoo. Int J Oncol 2014 May;44(5):1774-1780. "We show that WNT5A is upregulated in primary NPC tissue samples. We also demonstrate that WNT5A expression was dramatically increased in NPC cell lines expressing the EBV-encoded LMP2A gene, suggesting that this EBV-encoded latent gene is responsible for upregulating WNT5A in NPC. In addition, in vitro WNT5A overexpression promotes the proliferation, migration and invasion of NPC cells."

Yap - Int J Oncol 2014 abstract / PubMed

Epstein-Barr Virus Infection Induces Indoleamine 2,3-Dioxygenase Expression in Human Monocyte-Derived Macrophages through p38/Mitogen-Activated Protein Kinase and NF-κB Pathways: Impairment in T Cell Functions. WL Liu, YH Lin, H Xiao, S Xing, H Chen, PD Chi, G Zhang. J Virol 2014 Jun 15;88(12):6660-6671. "EBV infection induced mRNA, protein, and enzymatic activity of IDO in human monocyte-derived macrophages (MDMs). Infection increased the production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), whereas the neutralizing antibodies against TNF-α and IL-6 inhibited IDO induction. EBV infection also activated the mitogen-activated protein kinase (MAPK) p38 and NF-κB, and the inhibition of these two pathways with SB202190 and SN50 almost abrogated TNF-α and IL-6 production and inhibited IDO production. Moreover, the activation of IDO in response to EBV infection of MDMs suppressed the proliferation of T cells and impaired the cytotoxic activity of CD8+ T cells, whereas the inhibition of IDO activity with 1-methyl-l-tryptophan (1-MT) did not affect T cell proliferation and function."

Liu - J Virol 2014 abstract / PubMed

miR-31 is consistently inactivated in EBV-associated nasopharyngeal carcinoma and contributes to its tumorigenesis. CC Cheung, GT Chung, SW Lun, KF To, KW Choy, KM Lau, SP Siu, XY Guan, RK Ngan, TT Yip, P Busson, SW Tsao, KW Lo. Mol Cancer 2014 Aug 7;13(1):184. "Downregulation of miR-31 expression was detected in almost all NPC cell line, patient-derived xenografts (PDXs) and primary tumors. Both homozygous deletion and promoter hypermethylation were shown to be major mechanisms for miR-31 silencing in this cancer. Strikingly, loss of miR-31 was also obviously observed in the dysplastic lesions of nasopharynx. Restoration of miR-31 in C666-1 cells inhibited the cell proliferation, colony-forming and migratory capacities. Dramatic reduction of in vitro anchorage-independent growth and in vivo tumorigenic potential were demonstrated in the stable clones expressing miR-31. Furthermore, we proved that miR-31 suppressed the NPC cell growth via targeting FIH1 and MCM2."

Cheung - Mol Cancer 2014 full article / PubMed Central
Cheung / Mol Cancer 2014 full article

Characterization of the nasopharyngeal carcinoma methylome identifies aberrant disruption of key signaling pathways and methylated tumor suppressor genes. L Li, Y Zhang, Y Fan, K Sun, X Su, Z Du, SW Tsao, TK Loh, H Sun, AT Chan, YX Zeng, WY Chan, FK Chan, Q Tao. Epigenomics 2015 Apr;7(2):155-173. "Epigenetic disruption of Wnt, MAPK, TGF-β and Hedgehog signaling pathways was detected. Methylation of Wnt signaling regulators (SFRP1, 2, 4 and 5, DACT2, DKK2 and DKK3) was frequently detected in tumor and nasal swab samples from NPC patients. Functional studies showed that these genes are bona fide tumor-suppressor genes for NPC. Conclusion: The NPC methylome shows a special high-degree CpG methylation epigenotype, similar to the Epstein-Barr virus-infected gastric cancer, indicating a critical epigenetic etiology for NPC pathogenesis."

Li - Epigenomics 2015 abstract / PubMed

In-cell infection: a novel pathway for Epstein-Barr virus infection mediated by cell-in-cell structures. C Ni, Y Chen, M Zeng, R Pei, Y Du, L Tang, M Wang, Y Hu, H Zhu, M He, X Wei, S Wang, X Ning, M Wang, J Wang, L Ma, X Chen, Q Sun, H Tang, Y Wang, X Wang. Cell Res 2015 Jul;25(7):785–800. EBV-infected B cells invaded non-susceptible epithelial cells, forming cell-in-cell structures, which led to infection of the epithelial cells. "Such unique cellular structures could be readily observed in the specimens of nasopharyngeal carcinoma... Significantly, EBV generated from in-cell infected ECs displayed altered tropism with higher infection efficacy to both B cells and ECs."

Ni / Cell Res 2015 full article

EBV strain differences in NPC

EBV strain variation: geographical distribution and relation to disease state. M Abdel-Hamid, JJ Chen, N Constantine, M Massoud, N Raab-Traub. Virology 1992 Sep;190(1):168-175. "The predominant strains in nasopharyngeal carcinoma (NPC) from regions with elevated incidence were EBV type 1 in southeast Asia and Mediterranean Africa. In Alaskan Eskimos, a distinct variant of EBV type 2 was found in NPC and carcinoma of the parotid gland. This strain contained polymorphisms characteristic of the Asian EBV type 1. The strains prevalent in southeast Asia and Mediterranean Africa were also found in NPC which developed in caucasian Americans. These variants were not detected in lymphomas which developed in central Africa, Mediterranean Africa, or continental United States. These results suggest that distinct EBV strains predominate in geographic areas with elevated incidence of NPC [emphasis added]. The detection of these distinct strains in epithelial tumors from areas of low incidence may reflect an epithelial cell tropism or pathogenicity."

Abdel-Hamid et al. Virology 1992 abstract / PubMed

Frequent presence of subtype A virus in Epstein-Barr virus-associated malignancies. SC Peh, LH Kim, S Poppema. Pathology 2002 Oct;34(5):446-450. In 17 Hodgkin's, 14 Burkitt's, 4 T-cell and 3 B-cell non-Hodgkin's lymphomas, "All cases showed presence of type A virus, consistently detected with nested PCR protocol but not with single step PCR. There was no type B virus or mix infections detected."

Peh - Pathology 2002 abstract / PubMed

Glycoprotein gp110 of Epstein-Barr virus determines viral tropism and efficiency of infection. B Neuhierl, R Feederle, W Hammerschmidt, HJ Delecluse. Proc Natl Acad Sci USA 2002 Nov 12;99(23):15036-15041. "We show here that the EBV BALF4 gene product, the glycoprotein gp110, dramatically enhances the ability to infect human cells... Analysis of several virus isolates showed that the amount of BALF4 present within mature virions markedly differed among these strains... gp110 constitutes an important virulence factor that determines infection of non-B cells by EBV."

Neuhierl / PNAS 2002 Full Article
Neuhierl - PNAS 2002 Full Article / PubMed Central

Discrete alterations in the BZLF1 promoter in tumor and non-tumor-associated Epstein-Barr virus. MI Gutierrez, MM Ibrahim, JK Dale, TC Greiner, SE Straus, K Bhatia. J Natl Cancer Inst 2002 Dec 4;94(23):1757-1763. "Among the malignant samples, sequence Zp-P, associated with 84% of type A EBV, was identical to that of EBV strain B95.8, whereas a second sequence (Zp-V3), associated exclusively with type B EBV (P<.001), contained three base substitutions. Among the nonmalignant samples, a distinct polymorphism, Zp-V4, containing the substitutions detected in Zp-V3 and an additional base change, was identified in all samples from chronic active EBV, IM, and healthy individuals, but in none of the malignant samples (P<.001)."

Gutierrez - J Natl Cancer Inst 2002 abstract / PubMed
Gutierrez - J Natl Cancer Inst 2002 Full Article

Potential selection of LMP1 variants in nasopharyngeal carcinoma. RH Edwards, D Sitki-Green, DT Moore, N Raab-Traub. J Virol. 2004 Jan;78(2):868-881. "the strain-specific changes in HLA epitopes in LMP1 may enable its expression in the tumors without recognition by LMP1-specific CTL. In summary, the striking consistent sequence variation of LMP1 strains may contribute to the transformation of epithelial cells in NPC through reduced immune recognition and also through differences in molecular and biologic properties that are yet to be elucidated."

Edwards / J Virol. 2004 full article
Edwards - J Virol. 2004 full article / PubMed Central

Genomic Sequence Analysis of Epstein-Barr Virus Strain GD1 from a Nasopharyngeal Carcinoma Patient. M-S Zeng, D-J Li, Q-L Liu, L-B Song, M-Z Li, R-H Zhang, X-J Yu, H-M Wang, I Ernberg, and Y-X Zeng. J Virol. 2005 Dec;79(24):15323-15330. "To date, the only entire Epstein-Barr virus (EBV) genomic sequence available in the database is the prototype B95.8, which was derived from an individual with infectious mononucleosis. A causative link between EBV and nasopharyngeal carcinoma (NPC), a disease with a distinctly high incidence in southern China, has been widely investigated. However, no full-length analysis of any substrain of EBV from this area has been reported. In this study, we analyzed the entire genomic sequence of an EBV strain from a patient with NPC in Guangdong, China... We detected many sequence variations in GD1 compared to prototypical strain B95.8, including 43 deletion sites, 44 insertion sites, and 1,413 point mutations. Furthermore, we evaluated the frequency of some of these GD1 mutations in Cantonese NPC patients and found them to be highly prevalent. These findings suggest that GD1 is highly representative of the EBV strains isolated from NPC patients in Guangdong, China, an area with the highest incidence of NPC in the world. Furthermore, these findings provide the second full-length sequence analysis of any EBV strain as well as the first full-length sequence analysis of an NPC-derived EBV strain."

Zeng / J Virol 2005 full article

Differential gene regulation by Epstein-Barr virus type 1 and type 2 EBNA2. W Lucchesi, G Brady, O Dittrich-Breiholz, M Kracht, R Russ, PJ Farrell. J Virol 2008 Aug;82(15):7456-7466. "Microarray analysis of EBNA2 target genes identified a small number of genes that are more strongly induced by type 1 than by type 2 EBNA2, and one of these genes (CXCR7) was shown to be required for proliferation of lymphoblastoid cell lines. The Epstein-Barr virus LMP1 gene was also more strongly induced by type 1 EBNA2 than by type 2, but this effect was transient. Type 1 and type 2 EBNA2 were equally effective at arresting cell proliferation of Burkitt's lymphoma cell lines lacking Epstein-Barr virus and were also shown to cause apoptosis in these cells. The results indicate that differential gene regulation by Epstein-Barr virus type 1 and type 2 EBNA2 may be the basis for the much weaker B-cell transformation activity of type 2 Epstein-Barr virus strains compared to type 1 strains."

Lucchesi - J Virol 2008 abstract / PubMed

The dominance of China 1 in the spectrum of Epstein-Barr virus strains from Cantonese patients with nasopharyngeal carcinoma. DJ Li, JX Bei, SJ Mai, JF Xu, LZ Chen, RH Zhang, XJ Yu, MH Hong, YX Zeng, T Kang. J Med Virol 2009 Jul;81(7):1253-1260. Cantonese patients from Guangdong, "The results show that China 1 was the dominant EBV strain detected in both the tumor biopsies and samples of throat washings, whereas multiple strains, including China 1, China 2, B95-8, and Med, were detected in blood samples. In addition, a new strain named China 4 was found in blood samples."

Li - J Med Virol 2009 abstract / PubMed

Epstein-Barr virus latent gene sequences as geographic markers of viral origin: unique EBNA3 gene signatures identify Japanese viruses as distinct members of the Asian virus family. A Sawada, D Croom-Carter, O Kondo, M Yasui, M Koyama-Sato, M Inoue, K Kawa, A Rickinson, RJ Tierney. J Gen Virol 2011 May;92(Pt 5):1032-1043. "[W]hile Chinese viruses mainly fall into two families with strongly linked 'Wu' or 'Li' alleles at EBNA2 and EBNA3A/B/C, Japanese viruses all have the consensus Wu EBNA2 allele but fall into two families at EBNA3A/B/C."

Sawada - J Gen Virol 2011 abstract / PubMed

High Prevalence of the EBER Variant EB-8m in Endemic Nasopharyngeal Carcinomas. ZC Shen, B Luo, JN Chen, Y Chao, CK Shao, QQ Liu, Y Wang. PLoS One 2015 Mar 25;10(3):e0121420. "According to the phylogenetic tree, four EBER variants (EB-6m, EB-8m, EB-10m and B95-8) were identified. EB-6m was dominant in all population groups except for endemic NPC group, in which EB-8m was dominant. EB-8m was more common in endemic NPC cases (82.0%, 41/50) than non-endemic NPC cases (33.7%, 32/95) (p<0.0001), and it was also more frequent in healthy donors from endemic area (32.4%, 24/74) than healthy donors from non-endemic area (1.1%, 1/92) (p<0.0001). More importantly, the EB-8m was more prevalent in NPC cases than healthy donors in both areas (p<0.0001)."

Shen - PLoS One 2015 full article / PubMed Central
Shen / PLoS One 2015 full article

Sequence analysis of EBV immune evasion gene BNLF2a in EBV associated tumors and healthy individuals from nasopharyngeal carcinoma endemic and non-endemic regions of China. S Liu, X Wang, J Shu, Z Zhao, Z Sun, B Luo. J Med Virol 2015 Nov;87(11):1946-1952. "408 cases of EBV positive tumors (76 lymphomas, 45 gastric carcinomas, and 85 nasopharyngeal carcinomas in northern China and 27 lymphomas, 30 gastric carcinomas, and 57 nasopharyngeal carcinomas in southern China) and throat washings from healthy individuals (39 in northern China and 49 in southern China)... The variation patterns of BNLF2a were significantly different between samples from northern and southern China (P<0.05), and between the tumors and healthy donor samples from the northern China (P<0.0167). Type BNLF2a-B was more frequent in healthy donors of northern China (33.3%), and the proportion of this type was higher in the northern than in the southern NPCs."

Liu - J Med Virol 2015 abstract / PubMed

A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma. FT Feng, Q Cui, WS Liu, YM Guo, QS Feng, LZ Chen, M Xu, B Luo, DJ Li, LF Hu, JM Middeldorp, O Ramayanti, Q Tao, SM Cao, WH Jia, JX Bei, YX Zeng. Chin J Cancer 2015 Dec 16;34(3):61. A single nucleotide polymorphism (SNP) in the EBV genome (locus 155391: G>A, named G155391A) was associated with NPC in a combined analysis of 1109 cases and 2052 controls in 4 independent cohorts. "[T]he SNP G155391A was strongly associated with NPC (P combined < 0.001, OR = 5.27, 95% CI 4.31-6.44). Moreover, the frequency of the SNP G155391A was associated with NPC incidence but was not associated with the incidences of other EBV-related malignancies. Furthermore, the protein degradation assay showed that this SNP decreased the degradation of the oncogenic RPMS1 protein."

Feng - Chin J Cancer 2015 full article / PubMed Central
Feng / Chin J Cancer 2015 full article


Time and age trends for sinonasal cancer in Connecticut incidence and US mortality rates. GC Roush, MJ Schymura, JM Stevenson, TR Holford. Cancer 1987 Aug 1;60(3):422-428. "For the US mortality rates, from the 1875 to 1950 birth cohorts, there is a decline by more than twofold in men and more than threefold in women."

Roush - Cancer 1987 abstract / PubMed

Incidence and survival rates for young blacks with nasopharyngeal carcinoma in the United States. LM Richey, AF Olshan, J George, CG Shores, AM Zanation, T Cannon, MC Weissler. Arch Otolaryngol Head Neck Surg 2006 Oct;132(10):1035-40. Incidence of nasopharyngeal carcinoma among US black, white, and Asian/Pacific Islanders, diagnosed before age 29, from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) tumor registry. "From 1973 to 2002, incidence rates per 1 million persons, adjusted to the 2000 standard population, for blacks, whites, and Asians younger than 20 years with NPC were 1.61 (n=43), 0.61 (n=99), and 0.95 (n=18), respectively... From ages 20 to 29 years, rates increased slightly in blacks (1.87) and whites (0.96), while increasing dramatically in Asians (7.18)."

Richey - Arch Otolaryngol Head Neck Surg 2006 abstract / PubMed

Anti-smoking frauds

Nasopharyngeal cancer in a low-risk population: defining risk factors by histological type. TL Vaughan, JA Shapiro, RD Burt, GM Swanson, M Berwick, CF Lynch, JL Lyon. Cancer Epidemiol Biomarkers Prev 1996 Aug;5(8):587-593. This study claimed to find a risk among current smokers of more than 60 pack-years. However, the only EBV-related parameter considered was "diagnosis of infectious mononucleosis," which is associated with EBV infection later in life (whereas EBV infection early in life is characteristic of areas where NPC is endemic). They blow off the importance of EBV in this fashion: "A link between nasopharyngeal carcinoma and infection with the EBV is well documented. However, infection with EBV is a worldwide phenomenon; serological evidence points to its almost ubiquitous presence. Thus, even though the EBV infection appears to be a necessary factor in the development of many nasopharyngeal carcinomas, it is also clear that additional cofactors are required before a malignancy is expressed." This is the standard blow-off of health fascists. The supposed "additional cofactors" of interest to them include human genes but not EBV genes, and "lifestyle" bogeymen which do not include infection with EBV early in life, plus more frequent exposures thereafter.

Vaughan / Cancer Epidemiol Biomarkers Prev 1996 full article

The end of a fraud: The National Cancer Institute finally admits the truth

The NCI's CancerNet failed to mention Epstein-Barr virus in its discussion of "Paranasal Sinus and Nasal Cavity Cancer," for either health professionals (02/2000) or patients (05/2001). They said only that "Some data indicate that various industrial exposures may be related to cancer of the paranasal sinus and nasal cavity."

To patients, NCI now says that "Ethnic background and exposure to the Epstein-Barr virus can affect the risk of developing nasopharyngeal cancer." But they treat ethnicity and EBV as if they are merely equivalent "risk factors," with no acknowledgment that the first is non-causal while the second is causal. (Nasopharyngeal Cancer (PDQ): Treatment. General Information About Nasopharyngeal Cancer, Patient Version. Last Modified: 06/21/2005) While to professionals, they say, "Unlike other squamous cell cancers of the head and neck, nasopharyngeal cancer does not appear to be linked to excess use of tobacco and alcohol. Factors thought to predispose to this tumor include Chinese (or Asian) ancestry, Epstein-Barr virus (EBV) exposure, and as yet unknown factors that result in very rare familial clusters." (Nasopharyngeal Cancer (PDQ): Treatment. General Information. Health Professional Version. Last Modified: 03/22/2006)

Nasopharyngeal Cancer, Patient Version / National Cancer Institute
Nasopharyngeal Cancer, Health Professional Version / National Cancer Institute

The fraud of IARC Monograph 83 (Tobacco smoke and involuntary smoking. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans). IARC Monograph 83. Lyon: International Agency for Research on Cancer; 2004.)

Active smoking: "Although the interpretation of the results is complicated by small sample sizes, the different criteria used for the selection of controls and the problem of control groups with smoking-related diseases, the combined evidence shows an association between tobacco smoking and nasopharyngeal carcinoma in both endemic and non-endemic areas. Infection with Epstein-Barr virus (human herpesvirus 4), a major cause of nasopharyngeal carcinoma worldwide (IARC, 1997), has not been controlled for in any of the available studies [emphasis added](p. 361). However, it is unlikely that confounding by infection with Epstein-Barr virus would explain the observed association between tobacco smoking and risk for nasopharyngeal carcinoma." No justification is offered for this claim, which is unacceptable considering the strong relations of EBV as well as smoking to social class.

Passive smoking (ETS): Likewise, there were no studies of environmental tobacco smoke which considered the role of Epstein-Barr virus infection. The subject of EBV was not even addressed in this section.

Note that Jonathan M. Samet was Chairman of the IARC committee which produced the fraudulent Monograph 83, as well as the Senior Scientific Editor of the 2004 Surgeon General report. He has been a ringleader in every major anti-smoking offensive since the 1980s, including the Surgeon General reports, the corrupt EPA ETS report, and committing perjury in the Minnesota and federal tobacco lawsuits.

The fraud of "The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General" (2006)

In the section on "Nasal Sinus Cavity and Nasopharyngeal Carcinoma" (Chapter 7, Cancer Among Adults from Exposure to Secondhand Smoke, pages 480-482), there is no mention of Epstein-Barr virus (nor is there any mention of it within the entire chapter). They are automatically guilty of scientific fraud for ignoring a known-carcinogenic cause of these cancers, one which is involved in over 90% of cases, and which is known to have strong socioeconomic associations which cause confounding with smoking and passive smoking. They conclude that "The evidence is suggestive but not sufficient to infer a causal relationship between secondhand smoke exposure and a risk of nasal sinus cancer in nonsmokers," and "the evidence is inadequate to infer the presence or absence of a causal relationship between secondhand smoke exposure and a risk of nasopharyngeal cancer among nonsmokers." But they pretend that only "Larger studies with more complete information on secondhand smoke exposure are needed, and "other potential confounders," of which they list "occupational factors" only. Note that the politically-connected charlatan, Jonathan M. Samet, is the lead editor of this report as well.

Chapter 7, The Health Consequences of Involuntary Exposure to Tobacco Smoke / SurgeonGeneral.gov (pdf, 86pp)
Acknowledgements, The Health Consequences of Involuntary Exposure to Tobacco Smoke / SurgeonGeneral.gov (pdf, 10pp)

The frauds of 1) false negatives and 2) multivariate analysis: Independent effect of EBV and cigarette smoking on nasopharyngeal carcinoma: a 20-year follow-up study on 9,622 males without family history in Taiwan. WL Hsu, JY Chen, YC Chien, MY Liu, SL You, MM Hsu, CS Yang, CJ Chen. Cancer Epidemiol Biomarkers Prev 2009 Apr;18(4):1218-1226. 32 cases. They claimed that the OR for > or = 30 pack years of smoking was 3.0 (1.3-7.2), while the ORs for low vs high antibody levels were 9.5 (2.2-40.1) and 21.4 (2.8-161.7), whose magnitude can easily produce spurious results due to residual confounding, including by cohort effect. Most important, although other studies have proven that virtually all NPC is associated with EBV, in this study 21 of the 32 cases were negative for "Combination of VCA IgA/DNase," and used as the reference (Table 2)! So, these were false negatives, which reduced the ORs associated with EBV. And, they admit that "Only age and cigarette smoking were consistently associated with an increased prevalence of both anti-EBV seromarkers." So, the smokers were more likely to have been infected. Then, they deliberately misrepresent the term "independence," which actually describes only the behavior of statistical results, as evidence of biological causality, which it is not. In fact, cervical cancer studies that are flagrantly confounded by undetected HPV infection have frequently displayed this type of so-called "independence" for non-causal associations. These are merely the result of residual confounding.

Hsu / Cancer Epidemiol Biomarkers Prev 2009 full article

See also:

EBV & Socioeconomic Status
HPV Causes Head and Neck Cancers

Interactions between EBV and various carcinogens not found

Anti-smoker propagandists have been fear-mongering about so-called "tobacco-specific nitrosamines" since the late 1970s. They deceive the public by calling them "tobacco specific" when they are actually nicotine-specific, and in nonsmokers, ordinary foods such as potatoes and tomatoes can be significant sources of nicotine. Furthermore, after all these years, they have failed to establish any solid body of evidence implicating these substances even in cancer in tobacco users. Laboratory animals are the basis of the supposed carcinogenicity of these substances, but animals are not like humans in that it is easier to cause tumors in animals with chemical carcinogens. It demonstrates the health establishment's monomaniacal obsession with chemical carcinogenesis that it has taken so long to look for possible interactions with infection, which in these studies with EBV have turned out negative.

Evaluation of the effect of smokeless tobacco purified products and extracts on latent Epstein-Barr virus. HB Jenson, P Heard, MP Moyer. Toxicology 1999 Mar 1;133(1):35-42. "There does not appear to be an in vitro effect of smokeless-tobacco constituents on EBV-infected lymphocytes that may contribute to the development of oral cancers."

Jenson - Toxicology 1999 abstract / PubMed

Effects of smokeless tobacco and tumor promoters on cell population growth and apoptosis of B lymphocytes infected with epstein-barr virus types 1 and 2. HB Jenson, J Baillargeon, P Heard, MP Moyer. Toxicol Appl Pharmacol 1999 Oct 15;160(2):171-182. "The absence of significant effects with NNK and NNN suggest that these properties reside with other compounds present in tobacco extracts." The property in point is cell lysis, meaning death, which aborts carcinogenesis.

Jenson - Toxicol Appl Pharmacol 1999 abstract / PubMed

See Also:

Confounding By Infection
Epstein-Barr Virus Causes Lymphomas
EBV Causes Lymphoepithelioma-like Lung Cancer
Epstein-Barr Virus Causes Gastric Carcinoma
EBV & Socioeconomic Status
EBV Causes Interstitial Lung Disease
EBV and Other Diseases
HPV Causes Sinonasal Cancer
EBV Causes Multiple Sclerosis
Epstein-Barr Virus Causes Sjogren’s Syndrome
EBV Causes Lupus


cast 01-16-16