Epstein-Barr Virus Causes Gastric Carcinoma

Although at least 80% of stomach cancer is associated with Helicobacter pylori infection, there is a subset of cancers that are HP-negative. Epstein-Barr virus is now implicated as the cause of many of these. The proportion of cancers caused by each depends upon the proportion of each infection in various populations.

"EBV has been detected in the vast majority of gastric lymphoepithelial carcinomas and in a high proportion of lymphoepithelial carcinomas of the lung and salivary gland. A smaller proportion of gastric adenocarcinomas is also EBV-associated. EBV DNA has been detected occasionally in epithelial tumours at a wide variety of other anatomical sites. An etiological role for EBV in lymphoepithelial and adenocarcinomas has not been conclusively established." (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.)

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

Association of Epstein-Barr virus with undifferentiated gastric carcinomas with intense lymphoid infiltration. Lymphoepithelioma-like carcinoma. D Shibata, M Tokunaga, Y Uemura, E Sato, S Tanaka, LM Weiss. American Journal of Pathology 1991 Sep;139(3):469-474. "ISH that was performed in six of these [7] cases showed EBV genomes to be uniformly present in the carcinoma cells and not present in the reactive lymphoid infiltrate or normal gastric mucosa. PCR of a polymorphic EBV locus (lymphocyte-determined membrane antigen) showed that a single genotype was present in each gastric LELC, consistent with a clonal process. These findings suggest that some undifferentiated gastric carcinomas are EBV-related and that focal EBV infection occurs before transformation."

Shibata et al. / Am J Pathol 1991 abstract

Epstein-Barr virus-associated gastric adenocarcinoma. D Shibata, LM Weiss. American Journal of Pathology 1992 Apr;140(4):769-774. "EBV sequences were detected in 22 of 138 (16%) cases of typical gastric adenocarcinoma by polymerase chain reaction and in situ hybridization (ISH) techniques. The EBV genomes were specifically present within the gastric carcinoma cells in an even distribution. The EBV genomes were also present in adjacent dysplastic epithelium but were absent in surrounding lymphocytes, other normal stromal cells, intestinal metaplasia, and normal gastric mucosa. The EBV genomes in the infected gastric carcinoma cells are expressed as EBV RNA was detected by ISH. EBV was most often detected in gastric tumors from men (21%) compared with women (3%). Thus some cases of gastric adenocarcinoma are EBV- associated."

Shibata & Weiss / Am J Pathol 1992 abstract

Association of Epstein-Barr virus with gastric carcinoma with lymphoid stroma. K Oda, J Tamaru, T Takenouchi, A Mikata, M Nunomura, N Saitoh, H Sarashina, N Nakajima. American Journal of Pathology 1993 Oct;143(4):1063-1071. "Epstein-Barr virus (EBV) has been detected in lymphoepithelioma of nasopharynx and lymphoepitheliomalike carcinomas in various organs. To clarify the association of EBV with gastric carcinoma with lymphoid stroma, which often resembles lymphoepithelioma, the authors examined 22 such cases by polymerase chain reaction and in situ hybridization techniques. In 18 informative cases, EBV DNA was detected by polymerase chain reaction in 14 (77.8%) cases, including lymph node metastases. EBV RNA was detected within the nuclei of carcinoma cells by in situ hybridization in all cases that were positive by polymerase chain reaction. Infiltrating lymphocytes and normal epithelia adjacent to carcinoma were EBV-negative. Southern blot analysis indicated clonal proliferation of tumor cells and episomal form of EBV. These findings suggest that EBV infection occurs before transformation and may be related to oncogenesis of EBV-associated gastric carcinoma."

Oda et al. / Am J Pathol 1993 abstract

Epstein-Barr virus in gastric carcinoma. M Tokunaga, CE Land, Y Uemura, T Tokudome, S Tanaka, E Sato. American Journal of Pathology 1993 Nov;143(5):1250-1254. "... 999 gastric carcinomas observed in 970 consecutive cases from a large Japanese hospital. EBV involvement occurred in 6.9 percent of lesions, a significantly lower proportion than has been observed in a North American series. Involvement was significantly more frequent among males, in tumors in the upper part of the stomach, and in adenocarcinomas of the moderately differentiated tubular and poorly differentiated solid or medullary types. Almost all carcinomas with marked lymphoid stroma were EBV-positive. Positive lesions were characterized by the presence of uniform hybridized signals in almost all carcinoma cells and by their absence from adjacent non-neoplastic tissue." [A higher prevalence of H. pylori infection in Japan vs. North America explains the difference in proportions -cast]

Tokunaga et al. / Am J Pathol 1993 abstract

Epstein-Barr virus and carcinomas: rare association of the virus with gastric adenocarcinomas. DC Rowlands, M Ito, DC Mangham, G Reynolds, H Herbst, MT Hallissey, JWL Fielding, KM Newbold, EL Jones, LS Young, G Niedobitek. British Journal of Cancer 1993 Nov;68:1014–1019. 174 gastric carcinomas. EBV was detected in the tumour cells in all of six undifferentiated gastric carcinomas, but in only 3/168 typical gastric adenocarcinomas (1.8%), by ISH.

Rowlands / Brit J Cancer 1993 abstract/pdf landing

Epstein-Barr-virus-associated medullary carcinomas with lymphoid infiltration of the stomach. Y Takano, Y Kato, H Sugano. J Cancer Res Clin Oncol 1994;120(5):303-308. "The presence of GMCL exhibited a 2/1 male-to-female ratio and a 1/2 early-to-advanced cancer ratio, predominantly located in the cardia and corpus of the stomach (90%). The presence of EBV DNA could be proven in 28 out of 30 GMCL cases (93%) by the polymerase chain reaction method, and in 27 cases (90%) latent infection of EBV strictly limited to cancer cells was identified by in situ hybridization with RNA using an EBV-associated small RNAs (EBERs) probe."

Takano - J Cancer Res Clin Oncol 1994 abstract / PubMed

Epstein-Barr virus-associated gastric carcinoma and Epstein-Barr virus infection of the stomach. M Fukayama, Y Hayashi, Y Iwasaki, J Chong, T Ooba, T Takizawa, M Koike, S Mizutani, M Miyaki, K Hirai. Lab Invest 1994 Jul;71(1):73-81. "(definitely amplifiable EBV-DNA and positive EBER1-signal in the nuclei of carcinoma cells) was found in 8 of 72 gastric carcinomas (11%). The dominant genotype of EBV was type A (7/8), with type C (6/8), and F (8/8) restriction enzyme polymorphism, which are the predominant type of EBV found in throat washing of the general population in Japan."

Fukayama - Lab Invest 1994 abstract / PubMed

Epstein-Barr virus in gastric carcinoma and adjacent normal gastric and duodenal mucosa. S Shousha, YA Luqmani. J Clin Pathol 1994 Aug;47(8):695–698. 1 of 19 tumors (a lymphoepithelioma-like gastric carcinoma) was EBV-positive. "However, scattered EBV positive cells were seen in the normal gastric or duodenal mucosa bordering the tumours in seven out of 11 cases," which were usual adenocarcinomas.

Shousha - J Clin Pathol 1994 full article / PubMed Central

Monoclonal Epstein-Barr virus genomes but lack of EBV-related protein expression in different types of gastric carcinoma. G Ott, T Kirchner, HK Muller-Hermelink. Histopathology 1994 Oct;25(4):323-329. Transcribed EBER sequences were found in seven (18%) of 39 gastric carcinomas.

Ott - Histopathology 1994 abstract / PubMed

Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein. S Imai, S Koizumi, M Sugiura, M Tokunaga, Y Uemura, N Yamamoto, S Tanaka, E Sato and T Osato. Proc Natl Acad Sci USA 1994 Sep 13;91(19):9131-9135. "In 1000 primary gastric carcinomas, 70 (7.0%) contained Epstein-Barr virus (EBV) genomic sequences detected by PCR and Southern blots. The positive tumors comprised 8 of 9 (89%) undifferentiated lymphoepithelioma-like carcinomas, 27 of 476 (5.7%) poorly differentiated adenocarcinomas, and 35 of 515 (6.8%) moderately to well-differentiated adenocarcinomas... every keratin-positive epithelial malignant cell expressed EBV-determined nuclear antigen 1 (EBNA1) but did not significantly express CD45+ infiltrating leukocytes. A single fused terminal fragment was detected in each of the EBNA1-expressing tumors, thereby suggesting that the EBV-carrying gastric carcinomas represent clonal proliferation of cells infected with EBV. The carcinoma cells had exclusively EBNA1 but not EBNA2, -3A, -3B, and -3C; leader protein; and latent membrane protein 1 because of methylation. The patients with EBV-carrying gastric carcinoma had elevated serum EBV-specific antibodies. The EBV-specific cellular immunity was not significantly reduced; however, the cytotoxic T-cell target antigens were not expressed. These findings strongly suggest a causal relation between a significant proportion of gastric carcinoma and EBV, and the virus-carrying carcinoma cells may evade immune surveillance."

Imai et al. / PNAS 1994 full article

In situ detection of Epstein-Barr virus in gastric and colorectal adenocarcinomas. St Yuen, LP Chung, SY Leung, IS Luk, SY Chan, J Ho. Am J Surg Pathol 1994 Nov;18(11):1158-1163. EBER was highly expressed in 7 (9.5%) of 74 gastric adenocarcinomas, while normal gastric epithelium was EBV negative in all cases. "This pattern of positivity, together with negative normal gastric epithelium and positive metastatic tumor, suggested that EBV infection occurred in the dysplastic phase and that an apparent growth advantage was conferred by the EBV infection."

Yuen - Am J Surg Pathol 1994 abstract / PubMed

Epstein-Barr virus-associated gastric adenocarcinoma in Taiwan. HJ Harn, JY Chang, MW Wang, LI Ho, HS Lee, JH Chiang, WH Lee. Hum Pathol 1995 Mar;26(3):267-271. "Epstein-Barr virus was detected in six of 55 lesions (11%), a significantly lower proportion than has been observed in a North American series... These findings confirm and extend the results of Shibata et al. They also indicate that EBV infection might be related to oncogenesis not only in rare gastric cancers that resemble nasopharyngeal lymphoepithelioma but also in typical gastric adenocarcinoma."

Harn et al. Hum Pathol 1995 abstract / PubMed

Epstein-Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. ML Gulley, DR Pulitzer, PA Eagan, BG Schneider. Hum Pathol 1996 Jan;27(1):20-27. "EBER1 was detected in 11 of 95 (12%) of cases. When present, the virus was localized to malignant epithelial cells and to dysplastic gastric epithelium, but was not seen in normal-appearing gastric epithelium or intestinal metaplasia."

Gulley - Hum Pathol 1996 abstract / PubMed

[Epstein-Barr associated gastric carcinoma: the genetic alteration and the expression of CD44 variant]. JM Chong, M Fukuyama. Nippon Rinsho 1997 Feb;55(2):381-385. "EBV-encoded small RNA was found in nearly all of the carcinoma cells even at the intramucosal stage."

Chong - Nippon Rinsho 1997 abstract / PubMed

Morphological characteristics of Epstein-Barr virus-related early gastric carcinoma: a case-control study. J Arikawa, M Tokunaga, E Satoh, S Tanaka, CE Land. Pathol Int 1997 Jun;47(6):360-367. "A strong association between Epstein-Barr virus (EBV) and gastric carcinoma has been demonstrated by the uniform presence of EBV in all carcinoma cells, episomal monoclonality, elevated antibodies, and a unique 'lace pattern' in the mucosa..."

Arikawa - Pathol Int 1997 abstract / PubMed

Epstein-Barr virus-associated gastric cancer in Russia. SA Galetsky, VV Tsvetnov, CE Land, TA Afanasleva, NN Petrovichev, YE Gurtsevitch, M Tokunaga. Int J Cancer 1997 Dec 10;73(6):786-789. 18 of 206 (8.7%) of gastric carcinomas in the USSR revealed uniform EBER-1 expression restricted to the carcinoma cells.

Galetsky - Int J Cancer 1997 abstract / PubMed

Frequency of Epstein-Barr virus-associated gastric adenocarcinoma in Taiwan. LL Hsieh, PJ Lin, TC Chen, JT Ou. Cancer Lett 1998 Jul 17;129(2):125-129. EBV was detected in 17 (20.7%) of 82 gastric adenocarcinomas.

Hsieh et al. Cancer Lett 1998 abstract / PubMed

Microsatellite instability, Epstein-Barr virus, mutation of type II transforming growth factor beta receptor and BAX in gastric carcinomas in Hong Kong. SY Leung, ST Yuen, LP Chung, KM Chu, MP Wong, FJ Branicki, JC Ho. Br J Cancer 1999 Feb;79(3-4):582-588. Of 79 gastric carcinomas (61 EBV negative and 18 EBV positive), "high-level MIs were present regardless of the EBV status, and were found in a particular clinicopathological subset of gastric carcinoma patient," namely intestinal-type tumours (P = 0.03) and a more prominent lymphoid infiltrate (P = 0.04).

Leung - Br J Cancer 1999 abstract / PubMed

[Detection and characterization of gastric carcinoma associated with epstein-barr virus]. VE Gurtsevich, SA Galetskii, SN Nered, EV Novikova, LS Iakovlova, ChE Land, MI Davydov, AA Klimenkov, NN Petrovichev, M Tokunaga. Vesin Ross Akad Med Nauk 1999;(3):56-59. "EBV involvement was significantly more frequent among males,... and located in the upper stomach (cardia and middle part). Most EBV-positive GCs were characterized by great lymphoid compartment involvement. The findings of the distribution of EBV-positive GCs by sex, site, and histology are similar to those in Japan; however, the detection rate of EBV-positive cases in Russia is higher than that of Japan (6.7%) and lower than that in the USA (16%)." This is probably due to lower rates of Helicobacter pylori infection in the US than in Russia or Japan. Helicobacter pylori is less associated with cancers of the gastric cardia than with other sites, and rates of cancer of the cardia have been increasing in the United States for the last 20 or so years, especially in men.

Gurtsevich - Vesin Ross Akad Med Nauk 1999 abstract / PubMed

Epstein-Barr virus-associated gastric carcinoma in Mexico: analysis of 135 consecutive gastrectomies in two hospitals. R Herrera-Goepfert, E Reyes, M Hernandez-Avila, A Mohar, R Shinkura, C Fujiyama, S Akiba, Y Eizuru, Y Harada, M Tokunaga. Mod Pathol 1999 Sep;12(9):873-878. 11 (8.5%) of 135 gastric carcinomas in Mexico were EBER-1-positive.

Herrera-Goepfert - Mod Pathol 1999 abstract / PubMed

Loss of p16/CDKN2A tumor suppressor protein in gastric adenocarcinoma is associated with Epstein-Barr virus and anatomic location in the body of the stomach. BG Schneider, ML Gulley, P Eagan, JC Bravo, R Mera, J Geradts. Hum Pathol 2000 Jan;31(1):45-50. "Gastric adenocarcinomas (n = 125) were analyzed by immunohistochemistry for the presence of p16, the CDKN2A gene product. This protein was lost in 31 of 125 cases (25%), and loss was associated with location of the tumor in the body of the stomach (P = .001). Loss of p16 was also associated with the presence of Epstein-Barr virus (EBV) in tumor cells as determined by in situ hybridization (P = .022)."

Schneider - Hum Pathol 2000 abstract / PubMed

Epstein-Barr virus and gastric carcinoma in Western patients: comparison of pathological parameters and p53 expression in EBV-positive and negative cancers. F Chapel, B Fabiani, F Davi, M Raphael, M Tepper, G Champault, C Guettier. Histopathology 2000 Mar;36(3):252-261. In 56 gastric carcinomas, "EBERs transcripts were detected in seven cases overall: four cases of 52 conventional carcinomas (7. 7%) and three cases of four gastric carcinomas with lymphoid stroma (75%)."

Chapel - Histopathology 2000 abstract / PubMed

Epstein-Barr virus-specific antibodies in Epstein-Barr virus-positive and -negative gastric carcinoma cases in Japan. R Shinkura, N Yamamoto, C Koriyama, Y Shinmura, Y Eizuru, M Tokunaga. J Med Virol 2000 Apr;60(4):411-416. In serum samples from 64 and 59 patients with EBV-positive and -negative gastric carcinomas, respectively, and 73 healthy controls, the geometric mean titer (GMT) of VCA-IgG was higher in EBV-positive carcinoma cases than in EBV-negative carcinoma cases (P < 0.001).

Shinkura - J Med Virol 2000 abstract / PubMed

Epstein-Barr virus-associated gastric carcinomas: relation to Helicobacter pylori infection and genetic alterations. MS Wu, CT Shun, CC Wu, TY Hsu, MT Lin, MC Chang, HP Wang, JT Lin. Gastroenterology 2000 Jun;118(6):1031-1038. EBV was detected in 11 (100%) LELCs and in 19 (13.7%) of 139 common GCs.

Wu - Gastroenterology 2000 abstract / PubMed

Epstein-Barr virus in gastric carcinomas with lymphoid stroma. MS Chang, WH Kim, CW Kim, YI Kim. Histopathology 2000 Oct;37(4):309-315. In Koreans, EBV infection was found in 30 (67%) of gastric carcinoma with lymphoid stroma, and 10 tumours (3.4%) of non-GCLS (P < 0.05).

Chang - Histopathology 2000 abstract / PubMed

Epstein-Barr virus and gastric carcinoma. K Takada. Mol Pathol 2000 Oct;53(5):255-261. Review. "The Epstein-Barr virus (EBV) is detected in the tissue of about 10% of gastric carcinoma cases throughout the world. In each case, 100% of carcinoma cells are infected with EBV." "About 10% of gastric carcinomas throughout the world are monoclonal proliferations of EBV infected carcinoma cells. Gastric carcinoma is one of the most common carcinomas, and the worldwide occurrence of EBV positive gastric carcinoma is estimated at more than 50 000 cases/year."

Takada / Mol Pathol 2000 full article

Clinicopathologic characteristics of Epstein-Barr virus-incorporated gastric cancers in Korea. MS Chang, HS Lee, CW Kim, YI Kim, WH Kim. Pathol Res Pract 2001;197(6):395-400. 5.6% of 306 consecutive gastric carcinomas were EBV+ in Korea.

Chang - Pathol Res Pract 2001 abstract / PubMed

Circulating Epstein-Barr virus DNA in the serum of patients with gastric carcinoma. YM Lo, WY Chan, EK Ng, LY Chan, PB Lai, JS Tam, SC Chung. Clin Cancer Res 2001 Jul;7(7):1856-1859. EBV DNA in sera of 93-100% of EBV+ gastric carcinoma patients; also 23% of gastritis cases, versus 3.6% of apparently healthy controls.

Lo - Clin Cancer Res 2001 abstract / PubMed
Lo - Clin Cancer Res 2001 Full Article

Epstein-Barr virus involvement is mainly restricted to lymphoepithelial type of gastric carcinoma among various epithelial neoplasms. Y Kijima, S Hokita, S Takao, M Baba, S Natsugoe, H Yoshinaka, K Aridome, T Otsuji, T Itoh, M Tokunaga, Y Eizuru, T Aikou. J Med Virol 2001 Aug;64(4):513-518. 7.3% of 313 gastric carcinomas were EBV EBER-1+ in Japan.

Kijima - J Med Virol 2001 abstract / PubMed

Detection of Epstein-Barr virus in gastrectomy specimens. YA Luqmani, SO Linjawi, S Shousha. Oncol Rep 2001 Sep-Oct;8(5):995-999. 1/20 (5%) of gastric cancers were EBER+ in Kuwait.

Luqmani - Oncol Rep 2001 abstract / PubMed

Distinct chromosomal aberrations in epstein-barr virus-carrying gastric carcinomas tested by comparative genomic hybridization. A Zur Hausen, NC Van Grieken, GA Meijer, MA Hermsen, E Bloemena, SG Meuwissen, JP Baak, CJ Meijer, EJ Kuipers, AJ Van Den Brule. Gastroenterology 2001 Sep;121(3):612-618. "Loss of chromosome 4p (P < 0.001) and of 11p (P < 0.02) was exclusively restricted to EBV-carrying gastric carcinomas."

zur Hausen - Gastroenterology 2001 abstract / PubMed

Epstein-Barr virus-associated gastric carcinoma in Japanese Brazilians and non-Japanese Brazilians in Sao Paulo. C Koriyama, S Akiba, K Iriya, T Yamaguti, GS Hamada, T Itoh, Y Eizuru, T Aikou, S Watanabe, S Tsugane, M Tokunaga. Jpn J Cancer Res 2001 Sep;92(9):911-917.

Koriyama - Jpn J Cancer Res 2001 abstract / PubMed

Epstein-Barr virus in gastric carcinoma is associated with location in the cardia and with a diffuse histology: a study in one area of Chile. A Corvalan, C Koriyama, S Akiba, Y Eizuru, C Backhouse, M Palma, J Argandona, M Tokunaga. Int J Cancer 2001 Nov 15;94(4):527-530. 16.8% of 185 cases were EBV-positive.

Corvalan - Int J Cancer 2001 abstract / PubMed

Evidence of lyric infection of Epstein-Barr virus (EBV) in EBV-positive gastric carcinoma. Y Hoshikawa, Y Satoh, M Murakami, M Maeta, N Kaibara, H Ito, T Kurata, T Sairenji. J Med Virol 2002 Mar;66(3):351-359. EBV found in 14% of 21 cases.

Hoshikawa - J Med Virol 2002 abstract / PubMed

The Epstein-Barr virus-associated gastric carcinoma in Southern and Northern China. Z Hao, C Koriyama, S Akiba, J Li, X Luo, T Itoh, Y Eizuru, J Zou. Oncol Rep 2002 Nov-Dec;9(6):1293-1298. 9% of 198 gastric carcinomas in Guangzhou, and 6% of 180 in Shenyang, were positive for EBV-encoded small RNA (EBER) by ISH.

Hao - Oncol Rep 2002 abstract / PubMed

Epstein-Barr virus-associated gastric carcinoma in southern India: A comparison with a large-scale Japanese series. J Kattoor C Koriyama, S Akiba, T Itoh, S Ding, Y Eizuru, EK Abraham, B Chandralekha, NS Amma, MK Nair. J Med Virol 2002 Nov;68(3):384-389. 10 / 215 (5%) gastric cancers in Kerala, India, and 6.2% of 2011 in Japan were EBV-positive. All 10 strains from India were subtype A.

Kattoor - J Med Virol 2002 abstract / PubMed

Detection of Epstein-Barr virus in gastric carcinoma cells and surrounding lymphocytes. K Oda, K Koda, N Takiguchi, M Nunomura, K Seike, M Miyazaki. Gastric Cancer 2003;6(3):173-178. "EBV was detected in 5.2% of gastric carcinomas and in 24.7% of infiltrating lymphocytes by the ISH method. The high positive rate (21.6%) by the PCR method corresponds to the presence of the EBV genome in surrounding lymphocytes."

Oda - Gastric Cancer 2003 abstract / PubMed

Epstein-Barr virus (EBV) and gastric carcinoma in Malaysian patients. N Karim, G Pallesen. Malays J Pathol 2003 Jun;25(1):45-47. Five of 50 gastric carcinomas showed EBER intranuclear positivity in all tumour cells.

Karim - Malays J Pathol 2003 abstract / PubMed

Epstein-Barr virus-associated gastric carcinoma in Cali, Colombia. E Carrascal, C Koriyama, S Akiba, O Tamayo, T Itoh, Y Eizuru, F Garcia, M Sera, G Carrasquilla, MB Piazuelo, L Florez, JC Bravo. Oncol Rep 2003 Jul-Aug;10(4):1059-1062. 23 of 178 (13%) consecutive gastric carcinoma cases were EBV-positive.

Carrascal - Oncol Rep 2003 abstract / PubMed

Epstein-barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with epstein-barr virus-negative carcinoma. HS Lee, MS Chang, HK Yang, BL Lee, WH Kim. Clin Cancer Res 2004 Mar 1;10(5):1698-1705. 63 (5.6%) of 1127 consecutive gastric carcinomas were EBV-positive. "In comparison with EBV-negative carcinomas, EBV-positive carcinomas showed frequent loss of expression of p16, smad4, FHIT, and KAI-1 (kangai 1; P < 0.05), but retained the expression of APC (adenomatous polyposis coli), DCC (deleted in colorectal cancer), and some DNA repair proteins (P < 0.05). There was negative association between EBV infection and the expression of MUC1, MUC2, MUC5AC, p53, CEA, C-erbB2, and smad7."

Lee / Clin Cancer Res 2004 full article

Detection of Epstein-Barr virus by PCR and expression of LMP1, p53, CD44 in gastric cancer. MA Lee, YS Hong, JH Kang, KS Lee, JY You, KY Lee, CH Park. Korean J Intern Med 2004 Mar;19(1):43-47. "EBV was detected in 4 of 40 cases (10%). In 1 of 4 EBV-positive cases, EBV was also detected in a metastatic lymph node."

Lee - Korean J Intern Med 2004 abstract / PubMed

[Adenocarcinomas of the stomach and distal esophagus. Incidence and phenotypic characteristics of EBV-associated cases in the Lyons area, France.] R Kerroucha, V Hervieu, ML Chambonniere, F Mege-Lechevallier, G Poncet, J Boulez, P Taniere, JY Scoazec. Ann Pathol 2004 Jun;24(3):228-235. 5 / 85 gastric adenocarcinomas (5.8%) were found by in situ hybridization (EBER-1 and -2) and immunohistochemistry (LMP1 and EBNA-1).

Kerroucha - Ann Pathol 2004 abstract / PubMed

[Expression of Epstein-Barr virus genes in EBV-associated gastric carcinoma] Y Wang, B Luo, P Zhao, BH Huang. Ai Zheng 2004 Jul;23(7):782-787. 13 EBV positive samples in 185 gastric carcinomas (7.03%); no corresponding para-carcinomas were positive.

Wang - Ai Zheng 2004 abstract / PubMed
Wang / Ai Zheng 2004 full article (pdf, 6 pp)

Histology-specific gender, age and tumor-location distributions of Epstein-Barr virus-associated gastric carcinoma in Japan. C Koriyama, S Akiba, A Corvalan, E Carrascal, T Itoh, R Herrera-Goepfert, Y Eizuru, M Tokunaga. Oncol Rep 2004 Sep;12(3):543-547. "EBV-GCs accounted for 4.5% and 6.1% of 1,088 intestinal-type and 830 diffuse-type gastric carcinomas, respectively. Both intestinal- and diffuse-type EBV-GCs showed male predominance, but the observed gender difference was statistically significant only in diffuse-type carcinomas (P<0.001)."

Koriyama - Oncol Rep 2004 abstract / PubMed

Epstein-Barr virus infection and gastric carcinoma in Sao Paulo State, Brazil. LF Lopes, MM Bacchi, D Elgui-de-Oliveira, SG Zanati, M Alvarenga, CE Bacchi. Braz J Med Biol Res 2004 Nov;37(11):1707-1712. "EBV infection was found in 6 of 53 (11.32%) gastric carcinomas, mostly from male patients (66.7%), with a mean age of 59 years old. Most EBV-positive tumors were in gastric antrum. Two EBV-positive tumors (33.3%) were conventional adenocarcinomas, whereas four (66.7%) were classified as lymphoepithelioma-like carcinomas."

Lopes / Braz J Med Biol Res 2004 full article

Epstein-Barr virus-associated gastric carcinoma in Papua New Guinea. J Morewaya, C Koriyama, S Akiba, D Shan, T Itoh, Y Eizuru. Oncol Rep 2004 Nov;12(5):1093-1098. 2 out of 150 gastric cancers were positive for EBER.

Morewaya - Oncol Rep 2004 abstract / PubMed

Expression of Epstein-Barr virus genes in EBV-associated gastric carcinomas. B Luo, Y Wang, XF Wang, H Liang, LP Yan, BH Huang, P Zhao. World J Gastroenterol 2005 Feb 7;11(5):629-633. 11 / 172 (6.39%) gastric carcinoma tissues were EBV-positive by PCR-Southern blotting and ISH. No corresponding para-carcinoma tissues were positive (chi(2) = 9.0909, P = 0.0026).

Luo - World J Gastroenterol 2005 abstract / PubMed

Epstein-Barr virus-associated gastric carcinoma: Evidence of age-dependence among a Mexican population. R Herrera-Goepfert, S Akiba, C Koriyama, S Ding, E Reyes, T Itoh, Y Minakami, Y Eizuru. World J Gastroenterol 2005 Oct 21;11(39):6096-6103. In 330 consecutive, non-selected, primary gastric carcinomas, EBER-1 was detected in 24 (7.3%) cases (male/female ratio: 1.2/1).

Herrera-Goepfert - World J Gastroenterol 2005 full article

Correlation of Epstein-Barr virus and its encoded proteins with Helicobacter pylori and expression of c-met and c-myc in gastric carcinoma. B Luo, Y Wang, XF Wang, Y Gao, BH Huang, P Zhao. World J Gastroenterol 2006 Mar 28;12(12):1842-1848. "The positive rate of H pylori and EBV in 185 gastric carcinomas was 59.45% (110/185) and 7.03% (13/185) respectively... The positivity of H pylori in EBV-associated and EBV-negative gastric carcinomas was 46.15% (6/13) and 81.40%(104/172) respectively. There was no significant correlation between EBV and H pylori infection... H pylori-positive gastric carcinoma is predominant in antrum location, while EBVaGC has a tendency of predominance in cardia/body location."

Luo - World J Gastroenterol 2006 full article

Association of a distinctive strain of Epstein-Barr virus with gastric cancer. A Corvalan, S Ding, C Koriyama, E Carrascal, G Carrasquilla, C Backhouse, L Urzua, J Argandona, M Palma, Y Eizuru, S Akiba. Int J Cancer 2006 Apr 1;118(7):1736-1742. In tumor samples from 73 EBVaGC cases and throat washings from 329 healthy adults, "most of the EBVaGC cases harbor a distinctive EBV strain (type "i"/XhoI +), but in healthy donors, this strain was as common as other strains." The odds ratio for this strain was 9.0 (95% CI 1.2-69).

Corvalan - Int J Cancer 2006 abstract / PubMed

Epstein-Barr virus associated gastric carcinoma: a report from Iran in the last four decades. A Abdirad, S Ghaderi-Sohi, K Shuyama, C Koriyama, H Nadimi-Barforoosh, S Emami, A Mosavi-Jarrahi, A Nahvijou, S Akiba. Diagn Pathol 2007 Jul 15;2(1):25. 9 (3%) were EBV positive, out of 273 formalin fixed paraffin-embedded cases of gastric carcinoma.

Abdirad - Diagn Pathol 2007 full article / PubMed Central
Abdirad / Diagn Pathol 2007 full article

The clinical meaning of mucin phenotype and Epstein-Barr virus infection in gastric cancer. Y Nakamura, H Yanai, T Kitoh, Y Matsubara, A Hirano, T Okamoto, T Yoshida, J Nishikawa, K Okita. Hepatogastroenterology 2008 Jan-Feb;55(81):41-45. 3 out of 120 consecutive gastric cancer lesions were positive for EBER-1.

Nakamura - Hepatogastroenterology 2008 abstract / PubMed

Association of Epstein-Barr virus antibody levels with precancerous gastric lesions in a high-risk cohort. AJ Schetter, WC You, ET Lennette, MT Gail, CS Rabkin. Cancer Sci 2008 Feb;99(2):350-354. In 183 subjects from Linqu, China, with precancerous gastric lesions (chronic atrophic gastritis, intestinal metaplasia, and dysplasia). "Antibody titers did not differ significantly among histological diagnoses determined at the time of phlebotomy. However, subjects with dysplasia at follow up had significantly higher geometric mean antibody titers for both anti-VCA and anti-EBNA. Subjects with greater than median antibody levels were more likely to progress between examinations, especially in the subgroup with intestinal metaplasia at the time of phlebotomy (odds ratios [95% confidence intervals]: 5.7 [1.6-20] for anti-EBNA >or=1:320; 3.8 [1.0-15] for anti-VCA >or=1:640)."

Schetter - Cancer Sci 2008 abstract / PubMed

Relationship between EBV infection and expression of cellular proteins c-Myc, Bcl-2, and Bax in gastric carcinomas. MA Lima, MV Ferreira, MA Barros, MI Pardini, AC Ferrasi, RM Mota, SH Rabenhorst. Diagn Mol Pathol 2008 Jun;17(2):82-89. 8 / 100 gastric carcinomas in Fortaleza, Brazil, were positive for EBV by ISH.

Lima - Diagn Mol Pathol 2008 abstract / PubMed

Association of Helicobacter pylori and Epstein-Barr virus with gastric cancer and peptic ulcer disease. A Saxena, K Nath Prasad, U Chand Ghoshal, N Krishnani, M Roshan Bhagat, N Husain. Scand J Gastroenterol 2008;43(6):669-674. 348 adult patients (non-ulcer dyspepsia 241, peptic ulcer disease 45, gastric cancer 62) undergoing upper gastrointestinal endoscopy. "In patients with GC and PUD, EBV DNA was detected more often than in those with NUD (GC versus NUD - 82.3% versus 37.3%, p<0.001; PUD versus NUD - 75.5% versus 37.3%, p<0.001). H. pylori infection and EBV DNA detected in different groups of patients was as follows: 62.2% in PUD, 46.8% in GC and 29.5% in NUD. PUD and GC were significantly associated (p<0.001 and <0.05, respectively) with the presence of H. pylori infection and EBV DNA as compared with NUD."

Saxena - Scand J Gastroenterol 2008 abstract / PubMed

[Epstein-Barr virus infection and p16(INK4a) overexpression in gastric adenocarcinoma]. P Wang, Q Zhang, JF Yang, ZN Cheng, K Zhang, DH Yu. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2008 Aug;22(4):244-246. "EBV LMP-1 and p16 protein were detected in 30.9% (30/97) and in 63.91% (62/97) cases of gastric adenocarcinomas respectively."

Wang - Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2008 abstract / PubMed

High levels of Epstein-Barr virus DNA in latently infected gastric adenocarcinoma. JL Ryan, DR Morgan, RL Dominguez, LB Thorne, SH Elmore, M Mino-Kenudson, GY Lauwers, JK Booker, ML Gulley. Lab Invest 2009 Jan;89(1):80-90. "EBV DNA was detected by Q-PCR in 48/75 United States cancers (64%) and in 38/38 Central American cancers (100%), which was a significant difference. EBER was localized to malignant epithelial cells in 8/48 (17%) United States and 3/38 (8%) Central American cancers. Viral loads were considerably higher for EBER-positive vs EBER-negative cancers (mean 162 986 vs 62 EBV DNA copies per 100,000 cells)."

Ryan - Lab Invest 2009 abstract / PubMed
Ryan / Lab Invest 2009 full article

[Genotyping of Epstein-Barr virus in Epstein-Barr virus associated gastric carcinoma]. TT Yang, Y Wang, X Liu, X Li, ZC Pang, B Luo. Bing Du Xue Bao 2009 Jan;25(1):29-34. 17 / 236 gastric carcinomas were positive for EBV.

Yang - Bing Du Xue Bao 2009 abstract / PubMed

Characteristics of Epstein-Barr virus-associated gastric cancer: a study of 235 cases at a comprehensive cancer center in U.S.A. CD Truong, W Feng, W Li, T Khoury, Q Li, S Alrawi, Y Yu, K Xie, J Yao, D Tan. J Exp Clin Cancer Res 2009 Feb 3;28:14. 12 / 235 primary gastric cancer patients "had intranuclear expression of EBV. EBV staining was seen only in tumor cells and no detectable EBV was observed in normal gastric mucosa, intestinal metaplasia or stromal cells."

Truong - J Exp Clin Cancer Res 2009 full article / PubMed Central

EBV-associated gastric carcinoma in high- and low-incidence areas for nasopharyngeal carcinoma. T Boysen, M Mohammadi, M Melbye, S Hamilton-Dutoit, B Vainer, AV Hansen, J Wohlfahrt, J Friborg. Br J Cancer 2009 Aug 4;101(3):530-533. 106 cases in Greenland, and 106 cases in Denmark. "The prevalence rate of EBV-associated gastric carcinomas was 8.5% in both populations."

Boysen - Br J Cancer 2009 full article / PubMed Central
Boysen / Br J Cancer 2009 full article

Meta-Analysis Shows That Prevalence of Epstein-Barr Virus-Positive Gastric Cancer Differs Based on Sex and Anatomic Location. G Murphy, R Pfeiffer, MC Camargo, CS Rabkin. Gastroenterology 2009 Sep;137(3):824-833. Meta-analysis of 70 studies including 15,952 cases of gastric cancer assessed by in situ hybridization for EBV-encoded small RNA. "The pooled prevalence estimate of EBV-positivity was 8.7% (95% CI: 7.5, 10.0) overall, with a two-fold difference by sex: 11.1% (95% CI: 8.7, 14.1) of gastric cancer cases in males vs. 5.2% (95% CI: 3.6, 7.4) of cases in females. Tumors arising in the gastric cardia (13.6%) or corpus (13.1%) were more than twice as likely to be EBV-positive as those in the antrum (5.2%; p<0.01 for both comparisons). EBV-prevalence was four times higher (35.1%) for tumors in post-surgical gastric stump/remnants. Over 90% of lymphoepithelioma-like carcinomas were EBV-positive but only 15 studies reported any cases of this type; prevalence did not significantly differ between the more common diffuse (7.6%) and intestinal (9.5%) histologies. EBV-prevalence was similar in cases from Asia (8.3%), Europe (9.2%), and the Americas (9.9%)."

Murphy - Gastroenterology 2009 abstract / PubMed

Prevalence and characteristics of Epstein-Barr virus-associated gastric carcinomas in Tunisia. M Trimeche, F Ksiâa, S Ziadi, S Mestiri, M Hachana, RB Gacem, B Sriha, S Korbi. Eur J Gastroenterol Hepatol 2009 Sep;21(9):1001-1007. "EBV was detected by polymerase chain reaction in 36% of cases, whereas EBERs were detected in the tumor cells in only four cases (4.1%)."

Trimeche - Eur J Gastroenterol Hepatol 2009 abstract / PubMed

EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1. H Geddert, A Zur Hausen, HE Gabbert, M Sarbia. Anal Cell Pathol (2010) 2010 Jan 1;33(3):143-149. "EBER-transcripts were detected in 19.6% (18/92) of GC. EBV-positive GC revealed significantly more often gene hypermethylation of p16, p14 and APC (p<0.0001, p<0.0001 and p=0.02, respectively) than EBV-negative GC."

Geddert - Anal Cell Pathol 2010 abstract / PubMed

Association of distinctive Epstein-Barr virus variants with gastric carcinoma in Guangzhou, southern China. JN Chen, YG Ding, ZY Feng, HG Li, D He, H Du, B Wu, CK Shao. J Med Virol 2010 Apr;82(4):658-667. 45 out of 676 consecutive gastric carcinoma cases were positive for EBV; 93.3% were positive for EBNA1. "In the EBV genome polymorphism analysis, type A strain, prototype F, type I, XhoI-, and del-LMP1 variants were predominant among EBVaGC patients, accounting for 44 (97.8%), 37 (82.2%), 45 (100%), 34 (75.6%), and 42 (93.3%) cases, respectively. Moreover, a new hotspot mutation in the BamHI-W1/I1 boundary region (148,972 T --> C) was found in 39 (86.7%) of the 45 cases. The predominant EBV variants in EBVaGC in Guangzhou are prototype F, type I, and XhoI-, which are different from those in NPC in this area (predominant variant-type "f") and in EBVaGC in Latin American countries (predominant type "i" and XhoI+), suggesting that the EBV variants are not only geographically distributed but also disease restricted, and the pathogenic role of EBV in different EBV associated epithelial malignancies in different areas may be distinct."

Chen - J Med Virol 2010 abstract / PubMed

Epstein -Barr virus-associated gastric carcinoma among patients with pernicious anemia. T Boysen, J Friborg, K Stribolt, S Hamilton-Dutoit, S Goertz, J Wohlfahrt, M Melbye. Int J Cancer 2011 Dec 1;129(11):2756-2760. "In total, 186 samples (55 PA-GC and 131 nonPA-GC) were identified. EBV-associated gastric carcinoma (EBV-GC) was more common among PA-GC compared with nonPA-GC, adjusted odds ratio (OR) = 2.53 (CI 0.88; 7.14), p=0.08, with further adjustment for lymphocytic infiltrate OR=2.94 (0.99-8.67), p=0.05. Gastric carcinomas with signet-ring cell morphology were significantly less common in patients with PA-GC compared with nonPA-GC (OR =0.05, CI 0.01;0.24)."

Boysen - Int J Cancer 2011 abstract / PubMed

Expression of Epstein-Barr Virus Gene and Clonality of Infiltrated T Lymphocytes in Epstein-Barr Virus-associated Gastric Carcinoma. JM Lee, H Kim, SH Noh, WY Lee, SJ Kim, JH Park. Immune Netw 2011 Feb;11(1):50-58. "EBV specific DNA and EBERs RNA were detected in 4 out of 30 [13.3%] patients. RT-PCR analysis revealed that all 4 of EBV-positive tumor tissues expressed EBNA1 mRNA and BARTs and LMP2a was detected only one sample out of 4. However, the EBNA2 and LMP-1 transcripts were not detected in these tissues. CD8(+) T cells were the predominant population of infiltrating lymphocytes in the EBV-positive gastric carcinoma... EBV can be largely divided into two types (Type 1 and Type 2), which have a slightly different gene composition. The distribution of these two types is similar in healthy individuals. However, most of the EBV isolated from tumors is Type 1, so that Type 1 EBV is more involved in tumorigenesis compared with Type 2. EBV detected in all 4 samples in this study was also Type 1."

Lee - Immune Netw 2011 full article / PubMed Central

Zinc finger E-box binding factor 1 plays a central role in regulating Epstein-Barr virus (EBV) latent-lytic switch and acts as a therapeutic target in EBV-associated gastric cancer. J Zhao, H Jin, KF Cheung, JH Tong, S Zhang, MY Go, L Tian, W Kang, PP Leung, Z Zeng, X Li, KF To, JJ Sung, J Yu. Cancer 2012 Feb 15;118(4):924-936. "EBV infection was detected in 11.3% (80 of 711) of gastric cancers. The presence of EBV was associated with age, men, and intestinal type cancer."

Zhao - Cancer 2012 abstract / PubMed

Epstein-Barr virus DNA associated with gastric adenocarcinoma and adjacent non-cancerous mucosa in patients from Manaus, Brazil. PF de Aquino, PC Carvalho, JS da Gama Fischer, AQ de Souza, JS Viana, SR Chalub, AD de Souza, MG Carvalho. Genet Mol Res 2012 Dec 17;11(4):4442-4446. "EBV DNA was detected in 8/10 of the tumor cases and in none of the six control subjects. In the positively identified samples, EBV DNA was detected in five corresponding resection margins."

de Aquino - Genet Mol Res 2012 abstract / PubMed

Clinical significance of gastritis cystica profunda and its association with Epstein-Barr virus in gastric cancer. MG Choi, JY Jeong, KM Kim, JM Bae, JH Noh, TS Sohn, S Kim. Cancer 2012 Nov 1;118(21):5227-5233. 161 gastric cancer patients with GCP versus 10,657 without, by ISH. "The EBV-positive rate was significantly higher in the GCP group (31.1%) than in the non-GCP group (5.8%)."

Choi - Cancer 2012 abstract / PubMed

Non-detection of Epstein-Barr virus and Human Papillomavirus in a region of high gastric cancer risk indicates a lack of a role for these viruses in gastric carcinomas. XY Yuan, MY Wang, XY Wang, AY Chang, J Li. Genet Mol Biol 2013 Jul;36(2):183-184. 44 patients with chronic gastritis, 30 patients with peptic ulcer, and 24 subjects with gastric carcinomas. "Neither EBV nor HPV DNA was detected in [gastric mucosa] tissue from the patients."

Yuan - Genet Mol Biol 2013 abstract / PubMed
Yuan - Genet Mol Biol 2013 full article / PubMed Central

[Gastric carcinoma is the most frequent Epstein-Barr virus-associated malignancy.] T Boysen, J Friborg. Ugeskr Laeger 2013 Nov 18;175(47A). "Epstein-Barr virus (EBV) is associated with 8% of gastric carcinomas (GC) worldwide, being the most frequent EBV-associated malignancy with 80,000 new cases per year. The association is based on the presence of clonal EBV products in gastric tumour cells, and elevated EBV antibodies in pre-diagnostic sera. EBV-associated GC are twice as common in males and often associated to cancer in the cardia-region. Gastric surgery increases the risk significantly."

Boysen - Ugeskr Laeger 2013 abstract / PubMed

Evidence of epstein-barr virus association with gastric cancer and non-atrophic gastritis. JL Martínez-López, J Torres, M Camorlinga-Ponce, A Mantilla, YA Leal, EM Fuentes-Pananá. Viruses 2014 Jan 20;6(1):301-318. 75 GC samples, 147 from non-tumor tissue, 75 biopsies from non-atrophic gastritis. "10.67% of GC, 1.3% of non-tumor controls and 8% of gastritis samples were found positive. An EBER1 in situ hybridization showed EBV infection of epithelial cells in GC and in a third of NAG samples, while in the other NAGs infection was restricted to the mononuclear cell infiltrate. EBV-positive GCs were enriched in lace and cribriform patterns, while these rare patterns were not observed in EBV negative samples."

Martínez-López / Viruses 2014 full article landing

Case-case comparison of smoking and alcohol risk associations with epstein-barr virus-positive gastric cancer. MC Camargo, C Koriyama, K Matsuo, WH Kim, R Herrera-Goepfert, LM Liao; Eurgast-EPIC Group, J Yu, G Carrasquilla, JJ Sung, I Alvarado-Cabrero, J Lissowska, F Meneses-Gonzalez, Y Yatabe, T Ding, N Hu, PR Taylor, DR Morgan, ML Gulley, J Torres, S Akiba, CS Rabkin. Int J Cancer 2014 Feb;134(4):948-953. 2,648 gastric cancer patients from 11 studies with tumor EBV status assessed by in situ hybridization, of which 184 (7%) were EBV-positive; versus EBV-negative patient controls [comparison of characteristics of patients with Hp versus EBV-related gastric cancer - cast]. "In unadjusted analyses, the OR of EBV positivity with smoking was 2.2 (95% confidence interval [CI], 1.6-3.2). The OR was attenuated to 1.5 (95% CI, 1.01-2.3) by adjustment for the possible confounders."

Camargo - Int J Cancer 2014 abstract / PubMed

Correlation between DNA methyltransferases expression and Epstein-Barr virus, JC polyomavirus and Helicobacter pylori infections in gastric carcinomas. F Ksiaa, S Ziadi, RB Gacem, MB Dhiab, M Trimeche. Neoplasma 2014;61(6):710-717. 43 gastrc carcinoma samples. H. pylori, JCV and EBV were detected in 55.8%, 32.6% and 9%, respectively, with JCV and/or EBV infections in 37% overall. "H.pylori co-infection was found in 64.3% (9/14) of JCV positive cases and in 50% of EBV positive GC, without a reliable significant relationship." And, "infection with JCV and/or EBV was significantly correlated with increased expression of DNMT1 in GC (P= 0.05)."

Ksiaa - Neoplasma 2014 abstract / PubMed

Prevalence and ‍‍‍Characteristics of Epstein-barr Virus-associated Gastric Cancer in Iran. E Faghihloo, MR Saremi, M Mahabadi, H Akbari, E Saberfar. Arch Iran Med 2014 Nov;17(11):767-770. EBV was detected in six cases (6.66%) out of 90 gastric cancers. "According to anatomic location, EBV was detected in 4 out of 39 (10.25% ) gastric cancer were located in cardia and 2 out of 26 (7.69%) gastric cancer were located in middle/corpus."

Faghihloo - Arch Iran Med 2014 abstract / PubMed

Profiles of epstein-barr virus associated gastric carcinomas in brunei darussalam. RL Yen, PU Telisinghe, A Cunningham, MS Abdullah, CF Chong, VH Chong. Asian Pac J Cancer Prev 2014;15(23):10489-10493. 81 patients; LMP-1 by IHC. "Intestinal metaplasia and active H. pylori infection were detected in 40.7%and 30.9% respectively... EBV positivity (EBVaGC) was seen in 30.9%." "Addition of serum serology to indicate exposure may increase the number of H. pylori cases."

Yen / Asian Pac J Cancer Prev 2014 full article

Epstein-barr virus in gastro-esophageal adenocarcinomas - single center experiences in the context of current literature. V Genitsch, A Novotny, CA Seiler, D Kröll, A Walch, R Langer. Front Oncol 2015 Mar 26;5:73. "None of the EAC [esophageal adenocarcinomas] were positive for EBER. In contrast, we observed EBER positivity in 2/73 adenocarcinomas of the GEJ [gastro-esophageal junction] (2.7%) and 12/274 GC (4.4%)."

Genitsch - Front Oncol 2015 abstract / PubMed

Is gastric lymphoepithelioma-like carcinoma a special subtype of EBV-associated gastric carcinoma? New insight based on clinicopathological features and EBV genome polymorphisms. N Cheng, DY Hui, Y Liu, NN Zhang, Y Jiang, J HAN, HG Li, YG Ding, H Du, JN Chen, CK Shao. Gastric Cancer 2015 Apr;18(2):246-255. Ten (1.42 %) of 702 gastric carcinoma cases were identified as gastric LELC, in which eight (80 %) cases were EBV-positive. The clinicopathological characteristics and EBV latency pattern of EBV-positive gastric LELC were similar to those of ordinary EBVaGC... For EBNA1 polymorphisms, the V-leu and P-ala subtypes were predominant in EBV-positive gastric LELC, which is different from the predominant V-val subtype in ordinary EBVaGC."

Cheng - Gastric Cancer 2015 abstract / PubMed

Frequency of Epstein - Barr virus infection as detected by messenger RNA for EBNA 1 in histologically proven gastric adenocarcinoma in patients presenting to a tertiary care center in South India. ML Rymbai, VV Ramalingam, I Samarasan, BS Chandran, G Mathew, J Jerobin, AM Abraham, J Sachithanandham, R Kannangai R. Indian J Med Microbiol 2015 Jul-Sep;33(3):369-373. EBV was detected in 6% of 100 cases of gastric adenocarcinoma.

Rymbai - Indian J Med Microbiol 2015 abstract / PubMed

Features of Gastric Carcinoma with Lymphoid Stroma Associate with Epstein-Barr Virus. H Lim, YS Park, JH Lee, DH Son, JY Ahn, KS Choi, DH Kim, KD Choi, HJ Song, GH Lee, HY Jung, JH Kim, JH Yook, BS Kim. Clin Gastroenterol Hepatol 2015 Oct;13(10):1738-1744.e2. 236 / 274 (86.1%) tumors were EBV positive.

Lim - Clin Gastroenterol Hepatol 2015 abstract / PubMed

Genome-wide analysis of Epstein-Barr virus (EBV) isolated from EBV-associated gastric carcinoma (EBVaGC). Y Liu, W Yang, Y Pan, J Ji, Z Lu, Y Ke. Oncotarget 2016 Jan 26;7(4):4903-4914. EBV was detected in 15 (7.3%) of 206 gastric cancer cases.

Liu - Oncotarget 2016 abstract / PubMed

Prognostic value of Tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer. BW Kang, AN Seo, S Yoon, HI Bae, SW Jeon, OK Kwon, HY Chung, W Yu, JG Kim. Ann Oncol 2016 Mar;27(3):494-501. 120 out of 1318 (9.1%) consecutive gastric cancers were EBV-positive.

Kang - Ann Oncol 2016 abstract / PubMed

Validation and calibration of next-generation sequencing to identify Epstein-Barr virus-positive gastric cancer in The Cancer Genome Atlas. MC Camargo, R Bowlby, A Chu, CS Pedamallu, V Thorsson, S Elmore, AJ Mungall, AJ Bass, ML Gulley, CS Rabkin. Gastric Cancer 2016 Apr;19(2):676-681. 295 gastric tumor samples. "Empiric cutoffs of sequencing counts identified 26 (9 %) tumors as EBV positive. EBV positivity or negativity by molecular testing was confirmed by EBER-ISH in all but one tumor evaluated by both approaches (kappa = 0.91)."

Camargo - Gastric Cancer 2016 abstract / PubMed

Epstein-Barr virus infection serves as an independent predictor of survival in patients with lymphoepithelioma-like gastric carcinoma. BH Min, CH Tae, SM Ahn, SY Kang, SY Woo, S Kim, KM Kim. Gastric Cancer 2016 Jul;19(3):852-859. 124 out of 145 (85.5%) gastrectomy patients with LELC were positive for EBV.

Min - Gastric Cancer 2016 abstract / PubMed

Detection of Epstein-Barr Virus and Cytomegalovirus in Gastric Cancers in Kerman, Iran. Z Leila, SA Arabzadeh, RM Afshar, AA Afshar, HR Mollaei. Asian Pac J Cancer Prev 2016;17(5):2423-2428. EBV was detected in 10 cases (11.1%) of 90 GC tissues.

Leila - Asian Pac J Cancer Prev 2016 abstract / PubMed

Immunohistochemistry as a Surrogate for Molecular Subtyping of Gastric Adenocarcinoma. RS Gonzalez, S Messing, X Tu, LA McMahon, CL Whitney-Miller. Hum Pathol 2016 Oct;56:16-21. 7/104 (7%) of gastric adenocarcinomas were positive for EBER by ISH,.

Gonzalez - Hum Pathol 2016 abstract / PubMed

Epstein-Barr virus-associated gastric cancer reveals intratumoral heterogeneity of PIK3CA mutations. C Böger, S Krüger, HM Behrens, S Bock, J Haag, H Kalthoff, C Röcken. Ann Oncol 2017 May 1;28(5):1005-1014. 22/484 (4.5%) GCs were EBER-positive. "Intratumoral heterogeneity of EBER-positivity was found in 18% of EBVaGCs. Twenty-three GCs held PIK3CA mutations in hot spot regions of exon 9 or 20, being significantly more common in EBVaGCs (P < 0.001)."

Böger - Ann Oncol 2017 full article / PubMed Central

Prevalence and characteristics of Epstein-Barr virus-associated gastric carcinomas in Portugal. C Nogueira, M Mota, R Gradiz, MA Cipriano, F Caramelo, H Cruz, A Alarcăo, FC E Sousa, F Oliveira, F Martinho, JM Pereira, P Figueiredo, M Leităo. Infect Agent Cancer 2017 Jul 19;12:41. 82 cases, 33 controls. "EBV was detected by PCR in 90.2% of stomach cancer cases, whereas EBERs were detected in 11%... H. pylori infection was detected in 62.2% of the gastric cancers and 64.7% of these patients were CagA+. On the other hand, the H. pylori prevalence was higher in the EBV-negative gastric carcinomas (64.4%) than in those carcinoma cases with EBV+ (44.4%)."

Nogueira - Infect Agent Cancer 2017 full article / PubMed Central
Nogueira / Infect Agent Cancer 2017 full article

Differentiated tumor immune microenvironment of Epstein-Barr virus-associated and negative gastric cancer: implication in prognosis and immunotherapy. J Ma, J Li, Y Hao, Y Nie, Z Li, M Qian, Q Liang, J Yu, M Zeng, K Wu. Oncotarget 2017 May 16;8(40):67094-67103. 32/571 (5.3%) gastric cancers were EBV-positive.

Ma - Oncotarget 2017 full article / PubMed Central
Ma / Oncotarget 2017 full article

Association between Helicobacter pylori, Epstein-Barr virus, human papillomavirus and gastric adenocarcinomas. CRT de Souza, MCA Almeida, AS Khayat, EL da Silva, PC Soares, LC Chaves, RMR Burbano. World J Gastroenterol 2018 Nov 21;24(43):4928-4938. 302 gastric adenocarcinomas. H. pylori: 87%, EBV: 20%, HPV: 3%. 78% of the H. pylori-positive samples were also cagA+. Coinfections of H. pylori-cagA + and EBV were correlated with the most advanced tumor stages. "Although only 20% of the tumors were positive for EBV, infection with this virus was associated with distant metastasis."

de Souza - World J Gastroenterol 2018 full article / PubMed Central
de Souza / World J Gastroenterol 2018 full article

Multiple infections by EBV, HCMV and Helicobacter pylori are highly frequent in patients with chronic gastritis and gastric cancer from Southwest Mexico: An observational study. O Del Moral-Hernández, CA Castańón-Sánchez, S Reyes-Navarrete, DN Martínez-Carrillo, R Betancourt-Linares, H Jiménez-Wences, S de la Peńa, A Román-Román, D Hernández-Sotelo, G Fernández-Tilapa. Medicine (Baltimore) 2019 Jan;98(3):e14124. 106 chronic gastritis, 32 gastric cancer patients. " In chronic gastritis and gastric cancer EBV was found in 69.8% and 87.5%, HCMV in 52.8% and 53.1%, and H. pylori in 48.1% and 40.6%, respectively. In chronic gastritis, 53% of H. pylori patients were EBV and 33% were both EBV/HCMV; in gastric cancer, 92.3% of H. pylori-infected individuals were EBV and 46.1% were EVB/HCMV."

Del Moral-Hernández - Medicine (Baltimore) 2019 abstract / PubMed

Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications. C Martinez-Ciarpaglini, T Fleitas-Kanonnikoff, V Gambardella, M Llorca, C Mongort, R Mengual, G Nieto, L Navarro, M Huerta, S Rosello, D Roda, N Tarazona, S Navarro, G Ribas, A Cervantes. ESMO Open 2019 May 27;4(3):e000470. 13 (6%) of 246 cases were positive for EBV.

Martinez-Ciarpaglini - ESMO Open 2019 full article / PubMed Central
Martinez-Ciarpaglini / ESMO Open 2019 full article

[Clinicopathological and molecular characteristics of Epstein-Barr virus associated gastric cancer: a single center large sample case investigation]. Y Yang, YQ Liu, XH Wang, K Ji, ZW Li, J Bai, AR Yang, Y Hu, HB Han, ZY Li, ZD Bu, XJ Wu, LH Zhang, JF Ji. Beijing Da Xue Xue Bao Yi Xue Ban 2019 Jun 18;51(3):451-458. 163 (5.0%) of 3241 gastric cancers were EBV+.

Yang - Beijing Da Xue Xue Bao Yi Xue Ban 2019 abstract / PubMed

[Impact of the Epstein Barr virus on gastric cancer in Peru]. B Beltrán Gárate, A Camara, MDC Kapsoli Sánchez, D Castro Uriol, A Yábar Berrocal. Rev Gastroenterol Peru 2019 Oct-Dec;39(4):319-322. 8.4% of 111 cases were positive for EBV EBER by chromogenic in situ hybridization.

Beltrán Gárate - Rev Gastroenterol Peru 2019 abstract / PubMed

Prospective observation: Clinical utility of plasma Epstein-Barr virus DNA load in EBV-associated gastric carcinoma patients. MZ Qiu, CY He, SX Lu, WL Guan, F Wang, XJ Wang, Y Jin, FH Wang, YH Li, JY Shao, ZW Zhou, JP Yun, RH Xu. Int J Cancer 2020 Jan 1;146(1):272-280. 140/2760 (5.1%) of gastric carcinomas were infected with EBV.

Qiu - Int J Cancer 2020 abstract / PubMed

Low Epstein-Barr Virus Prevalence in Cardia Gastric Cancer Among a High-Incidence Chinese Population. JG Aversa, M Song, N Hu, AM Goldstein, SM Hewitt, ML Gulley, S Dawsey, M Constanza Camargo, PR Taylor, CS Rabkin. Dig Dis Sci 2020 May 4 [Epub ahead of print]. 4% of 1035 adult gastric adenocarcinomas were EBV positive by ISH.

Aversa - Dig Dis Sci 2020 abstract / PubMed


Epstein-Barr Virus and methylation of the p16 gene

Epstein-Barr Virus-Positive Gastric Carcinoma Demonstrates Frequent Aberrant Methylation of Multiple Genes and Constitutes CpG Island Methylator Phenotype-Positive Gastric Carcinoma. GH Kang, S Lee, WH Kim, HW Lee, JC Kim, M-G Rhyu, JY Ro. American Journal of Pathology. 2002 Mar;160(3):787-794. "EBV-positive GCs showed simultaneous methylation of multiple genes involved in several molecular pathways in gastric carcinogenesis, including cell cycle regulation (p16, p14, 14-3-3 sigma, and COX2), DNA repair and protection (hMLH1, MGMT, and GSTP1), cell adherence and metastasis (E-cadherin and TIMP-3), angiogenesis (THBS1), apoptosis (DAP-kinase), and signal transduction (APC, PTEN, and RASSF1A). The average number of methylated MINT loci was significantly greater in EBV-positive GCs than in EBV-negative GCs."

Kang / Am J Pathol 2002 full article

Epstein-barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with epstein-barr virus-negative carcinoma. HS Lee, MS Chang, HK Yang, BL Lee, WH Kim. Clin Cancer Res 2004 Mar 1;10(5):1698-1705. 63 (5.6%) of 1127 consecutive gastric carcinomas were EBV-positive. "In comparison with EBV-negative carcinomas, EBV-positive carcinomas showed frequent loss of expression of p16, smad4, FHIT, and KAI-1 (kangai 1; P < 0.05), but retained the expression of APC (adenomatous polyposis coli), DCC (deleted in colorectal cancer), and some DNA repair proteins (P < 0.05). There was negative association between EBV infection and the expression of MUC1, MUC2, MUC5AC, p53, CEA, C-erbB2, and smad7."

Lee / Clin Cancer Res 2004 full article

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

The Epstein-Barr Virus Protein BMRF1 Activates Gastrin Transcription. EA Holley-Guthrie, WT Seaman, P Bhende, JL Merchant, SC Kenney. J Virol 2005 Jan;79(2):745-755. "Furthermore, as the EBV genome is present in up to 10% of gastric cancers, and the different forms of gastrin are growth factors for gastrointestinal epithelium, our results suggest a mechanism by which lytic EBV infection could promote the growth of gastric cells."

Holley-Guthrie - J Virology 2005 abstract
Holley-Guthrie / J Virology 2005 full article

Relationship between abnormality of FHIT gene and EBV infection in gastric cancer. Y-P Xiao, C-B Han, X-Y Mao, J-Y Li, L Xu, C-S Ren, Y Xin. World J. Gastroenterol 2005 Jun 7;11(21):3212-3216. "EBV was detected in 5/50 (10%) gastric cancers, among which 4/5 (80%) had aberrant transcripts of FHIT [fragile histidine triad] gene."

Xiao - World J Gastroenterol 2005 full article

Down-regulation of locus-specific human lymphocyte antigen class I expression in Epstein-Barr virus-associated gastric cancer: implication for viral-induced immune evasion. N Dutta, A Gupta, DN Mazumder, S Banerjee. Cancer 2006 Apr 15;106(8):1685-1693. "The current results suggested that the establishment of EBV latent infection in gastric tissues allows malignant cells to avoid the immune surveillance of both cytotoxic T-lymphocytes and natural killer cells by regulating the differential expression of HLA class I molecules. 2006 American Cancer Society."

Dutta - Cancer 2006 abstract / PubMed

p73 gene promoter methylation in Epstein-Barr virus-associated gastric carcinoma. T Ushiku, JM Chong, H Uozaki, R Hino, MS Chang, M Sudo, BR Rani, K Sakuma, H Nagai, M Fukayama. Int J Cancer 2007 Jan 1;120(1):60-66. "Loss of p73 expression by immunohistochemistry was specific to EBV-associated GC (11/13) compared to EBV-negative GC (3/38), which was independent of abnormal p53 expression. With methylation-specific polymerase chain reaction (MSP), the aberrant methylation of p73 exon 1 was similarly specific to EBV-associated GC (12/13), and also rare in EBV-negative GC (2/38). Bisulfite sequencing for p73 exon 1 and its 5' region confirmed the MSP results, showing uniform and high-density methylation in EBV-associated GC."

Ushiku - Int J Cancer 2007 abstract / PubMed

Epstein-Barr virus and gastric carcinoma--viral carcinogenesis through epigenetic mechanisms. H Uozaki, M Fukayama. Int J Clin Exp Pathol 2008 Jan 1;1(3):198-216. Review. "The most characteristic abnormality is global and non-random CpG island methylation of the promoter region of many cancer-related genes, which causes downregulation of their expression. This abnormality is accompanied by methylation of the EBV genome, suggesting virus-driven hypermethylation."

Uozaki & Fukayama - Int J Clin Exp Pathol 2008 full article / PubMed Central

Epstein-Barr virus upregulates phosphorylated heat shock protein 27 kDa in carcinoma cells using the phosphoinositide 3-kinase/Akt pathway. Y Fukagawa, Nishikawa J, Kuramitsu Y, Iwakiri D, Takada K, Imai S, Satake M, Okamoto T, Fujimoto M, Okita K, Nakamura K, Sakaida I. Electrophoresis 2008 Aug;29(15):3192-3200. One EBV-infected and one non-infected gastric carcinoma cell lines. "We found that EBV infection upregulated one of the phosphorylated heat shock protein 27 kDa (HSP27). The phosphorylated HSP27 isoform which increased in EBV(+) cells can be induced by both heat shock and arsenite. The increase of phosphorylated HSP27 in EBV(+) cells was reduced by treatment with the phosphoinositide 3-kinase (PI3K) inhibitors (LY294002 and wortmannin). In addition, we found increased levels of phosphorylated Akt in EBV(+) cells. These findings suggest that EBV infection upregulates the phosphorylation of HSP27 via the PI3K/Akt pathway. Thus, activation of the PI3K/Akt pathway may contribute to the establishment of a malignant phenotype in EBV-infected gastric carcinomas."

Fukagawa - Electrophoresis 2008 abstract / PubMed

Epstein-Barr virus-specific methylation of human genes in gastric cancer cells. JL Ryan, RJ Jones, SC Kenney, AG Rivenbark, W Tang, ER Knight, WB Coleman, ML Gulley. Infect Agent Cancer 2010 Dec 31;5:27. "In array studies, nearly half of the 96 human genes tested, representing 15 different cancer-related signal transduction pathways, were dysregulated after EBV infection. Reverse transcription PCR confirmed significant impact on factors having diverse functions such as cell cycle regulation (IGFBP3, CDKN2A, CCND1, HSP70, ID2, ID4), DNA repair (BRCA1, TFF1), cell adhesion (ICAM1), inflammation (COX2), and angiogenesis (HIF1A). Demethylation using 5-aza-2'-deoxycytidine reversed the EBV-mediated dysregulation for all 11 genes listed here."

Ryan - Infect Agent Cancer 2010 full article / PubMed Central
Ryan / Infect Agent Cancer 2010 full article

Contributions of the Epstein-Barr Virus EBNA1 Protein to Gastric Carcinoma. N Sivachandran, CW Dawson, LS Young, FF Liu, J Middeldorp, L Frappier. J Virol 2012;86(1):60-68. "AGS GC cells infected with EBV were found to contain fewer PML NBs and less PML proteins than the parental EBV-negative AGS cells, and these levels were restored by silencing EBNA1. Conversely, EBNA1 expression was sufficient to induce the loss of PML NBs and proteins in AGS cells. Consistent with PML functions, EBNA1 expression decreased p53 activation and apoptosis in response to DNA damage and resulted in increased cell survival. In addition, EBNA1 mutants unable to bind CK2 kinase or ubiquitin specific protease 7 had decreased ability to induce PML loss and to interfere with p53 activation. PML levels were then compared in EBV-positive and EBV-negative GC biopsies by immunohistochemistry. Consistent with the results in the AGS cells, EBV-positive tumours had significantly lower PML levels compared to EBV-negative tumours. The results indicate that EBV infection of GC cells leads to loss of PML NBs through the action of EBNA1, resulting in impaired responses to DNA damage and promotion of cell survival."

Sivachandran - J Virol 2012 abstract / PubMed

CpG island hypermethylation in gastric carcinoma and its premalignant lesions. GH Kang. Korean J Pathol 2012 Feb;46(1):1-9. Review. "Helicobacter pylori and Epstein-Barr virus, which are known carcinogens for gastric cancer, are closely associated with enhanced hypermethylation of CpG island loci in gastric non-neoplastic epithelial cells and cancer cells, respectively. Aberrant CpG island hypermethylation occurs early in the multistep cascade of gastric carcinogenesis and tends to increase with the step-wise progression of the lesion. Approximately 400 genes that are actively expressed in normal gastric epithelial cells are estimated to be inactivated in gastric cancers as a result of promoter CpG island hypermethylation."

Kang / Korean J Pathol 2012 full article (pdf, 9pp)
Kang - Korean J Pathol 2012 full article / PubMed Central

Epstein-barr virus infected gastric adenocarcinoma expresses latent and lytic viral transcripts and has a distinct human gene expression profile. W Tang, DR Morgan, MO Meyers, RL Dominguez, E Martinez, K Kakudo, PF Kuan, N Banet, H Muallem, K Woodward, O Speck, ML Gulley. Infect Agent Cancer 2012 Aug 28;7(1):21. "In 182 tissues with adequate housekeeper RNAs, distinct profiles were found in infected versus uninfected cancers, and in malignant versus adjacent benign mucosa. EBV-infected gastric cancers expressed nearly all of the 18 latent and lytic EBV RNAs in the test panel. Levels of EBER1 and EBER2 RNA were highest and were proportional to the quantity of EBV genomes as measured by Q-PCR. Among protein coding EBV RNAs, EBNA1 from the Q promoter and BRLF1 were highly expressed while EBNA2 levels were low positive in only 6/14 infected cancers. Concomitant upregulation of cellular factors implies that virus is not an innocent bystander but rather is linked to NFKB signaling (FCER2, TRAF1) and immune response (TNFSF9, CXCL11, IFITM1, FCRL3, MS4A1 and PLUNC), with PPARG expression implicating altered cellular metabolism. Compared to adjacent non-malignant mucosa, gastric cancers consistently expressed INHBA, SPP1, THY1, SERPINH1, CXCL1, FSCN1, PTGS2 (COX2), BBC3, ICAM1, TNFSF9, SULF1, SLC2A1, TYMS, three collagens, the cell proliferation markers MYC and PCNA, and EBV BLLF1 while they lacked CDH1 (E-cadherin), CLDN18, PTEN, SDC1 (CD138), GAST (gastrin) and its downstream effector CHGA (chromogranin). Compared to lymphoepithelioma-like carcinoma of the uterine cervix, gastric cancers expressed CLDN18, EPCAM, REG4, BBC3, OLFM4, PPARG, and CDH17 while they had diminished levels of IFITM1 and HIF1A."

Tang / Infect Agent Cancer 2012 full article

Expression profile of latent and lytic transcripts of epstein-barr virus in patients with gastroduodenal diseases: a study from northern India. SK Shukla, KN Prasad, A Tripathi, UC Ghoshal, N Krishnani, N Husain. J Med Virol 2012 Aug;84(8):1289-1297. 200 patients (10 dyspepsia, 30 peptic ulcer, 50 gastric cancer). "EBNA1 transcript was detected in all EBV positive cases and its expression was neither associated with disease nor with histopathological findings. The expression of BZLF1 was significantly associated with gastric cancer and peptic ulcer compared to dyspepsia (P < 0.01). BZLF1 expression was also found to be higher in Helicobacter pylori infected patients (P = 0.058). Expression of BARF1 and BcLF1 were significantly higher in gastric epithelium of patients having severe grade chronic inflammation (P = 0.05) and gastric atrophy (P = 0.02), respectively."

Shukla - J Med Virol 2012 abstract / PubMed

Epigenetic silencing of WNT5A in Epstein-Barr virus-associated gastric carcinoma. X Liu, Y Wang, X Wang, Z Sun, L Li, Q Tao, B Luo. Arch Virol 2013 Jan;158(1):123-132. 5 EBV-positive and 15 EBV-negative GC cell lines, and 23 EBV-positive and 25 EBV-negative paired tumor/normal tissue samples. "EBV-positive GC had no or very low expression of WNT5A but a high level of methylation in the promoter region. In contrast, EBV-negative GC had higher WNT5A expression and a lower level of promoter methylation. The reduced WNT5A expression could be restored by treatment with Aza, a methyltransferase inhibitor."

Liu - Arch Virol 2013 abstract / PubMed

Role of DNA methylation in the development of Epstein-Barr virus-associated gastric carcinoma. M Saito, J Nishikawa, T Okada, A Morishige, K Sakai, M Nakamura, S Kiyotoki, K Hamabe, T Okamoto, A Oga, K Sasaki, Y Suehiro, Y Hinoda, I Sakaida. J Med Virol 2013 Jan;85(1):121-127. 25 EBV-associated and 50 EBV-negative gastric carcinomas. "Methylation frequencies of 12 of the 16 genes were higher in EBV-associated gastric carcinomas than in EBV-negative controls, and the frequency of methylation of 6 specific loci (MINT2, MINT31, p14, p16, p73, and RUNX3) was significantly higher in EBV-associated gastric carcinomas than in EBV-negative controls. There were no significant differences in the methylation frequencies of the other genes."

Saito - J Med Virol 2013 abstract / PubMed

Genome-wide identification of Epstein-Barr virus-driven promoter methylation profiles of human genes in gastric cancer cells. J Zhao, Q Liang, KF Cheung, W Kang, RW Lung, JH Tong, KF To, JJ Sung, J Yu. Cancer 2013 Jan 15;119(2):304-312. 1065 genes were differentially methylated, "(83.2%, 886 of 1065 genes) had cytosine-guanine dinucleotide (CpG) hypermethylation in AGS-EBV (fold-changes 2.43∼65.2) versus that found in AGS cells. Gene ontology analysis revealed that hypermethylated genes were enriched in the important cancer pathways (≥ 10 genes each, P ≤ .05) including mitogen-activated protein kinase signaling, cell adhesion molecules, wnt signaling pathway, and so forth. Six novel hypermethylated candidates (IL15RA, REC8, SSTR1, EPHB6, MDGA2, and SCARF2) were further validated... Furthermore, these candidates were silenced or down-regulated in AGS-EBV cells, but can be restored by demethylation treatment."

Zhao - Cancer 2013 abstract / PubMed

The Epstein-Barr virus nuclear antigen-1 reprograms transcription by mimicry of high mobility group A proteins. G Coppotelli, N Mughal, S Callegari, R Sompallae, L Caja, MS Luijsterburg, NP Dantuma, A Moustakas, MG Masucci. Nucleic Acids Res 2013 Mar 1;41(5):2950-2962. "We found that the expression of EBNA1 in transfected human and mouse cells is associated with decreased prevalence of heterochromatin foci, enhanced accessibility of cellular DNA to micrococcal nuclease digestion and decreased average length of nucleosome repeats, suggesting de-protection of the nucleosome linker regions... [B]y regulating chromatin compaction, EBNA1 may reset cellular transcription during infection and prime the infected cells for malignant transformation." They speculate that this effect could underlie the association of the virus with malignancies such as gastric carcinoma that express EBNA1-only latency programs and arise in cells and tissues that are normally not susceptible to EBV infection.

Coppotelli - Nucleic Acids Res 2013 full article / PubMed Central

Epstein-Barr virus induced epigenetic alterations following transient infection. KJ Queen, M Shi, F Zhang, U Cvek, RS Scott. Int J Cancer 2013 May 1;132(9):2076-2086. "Decreased histone 3 or 4 acetylation at the promoter and 5' end of the E-cadherin gene was observed in an EBV-negative, transiently infected clone relative to the uninfected controls. These results suggest that EBV can stably alter gene expression in a heritable fashion in formerly infected cells, while its own contribution to the oncogenic process is masked."

Queen - Int J Cancer 2012 abstract / PubMed

Differences in Gastric Carcinoma Microenvironment Stratify According to EBV Infection Intensity: Implications for Possible Immune Adjuvant Therapy. MJ Strong, G Xu, J Coco, C Baribault, DS Vinay, MR Lacey, AL Strong, TA Lehman, MB Seddon, Z Lin, M Concha, M Baddoo, M Ferris, KF Swan, DE Sullivan, ME Burow, CM Taylor, EK Flemington. PLoS Pathog 2013 May;9(5):e1003341. 71 patients. "In addition to the finding that EBV is associated with down-regulated tumor regulatory genes, this study revealed that samples with high levels of EBV gene expression (hiEBVaGCs) displayed elevated immune cell infiltration with high interferon-gamma (IFNG) expression compared to samples with low or no EBV gene expression. Despite this evidence of increased immune posturing, hiEBVaGC samples also showed elevated expression of the potent immune cell inhibitor, IDO1. This finding may partly explain the persistence of these virus associated tumors in the face of local immune cell concentration."

Strong - PLoS Pathog 2013 full article / PubMed Central
Strong / PLoS Pathog 2013 full article

Identification of genes specifically methylated in Epstein-Barr virus-associated gastric carcinomas. T Okada, M Nakamura, J Nishikawa, K Sakai, Y Zhang, M Saito, A Morishige, A Oga, K Sasaki, Y Suehiro, Y Hinoda, I Sakaida. Cancer Sci 2013 Oct;104(10):1309-1314. 75 primary gastric cancer tissues from 25 patients with EBVaGC and 50 EBV-negative patients as controls. "Methylation frequencies of TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1 were significantly higher in EBVaGCs than in EBV-negative gastric carcinoma. We identified 7 genes whose promoter regions were specifically methylated in EBVaGCs. Inactivation of these genes may suppress their function as tumor suppressor genes or tumor-associated antigen to develop and maintain EBVaGCs."

Okada - Cancer Sci 2013 abstract / PubMed

Epstein-Barr Virus-Encoded BARF1 Promotes Proliferation of Gastric Carcinoma Cells through Regulation of NF-κB. MS Chang, DH Kim, JK Roh, JM Middeldorp, YS Kim, S Kim, S Han, CW Kim, BL Lee, WH Kim, JH Woo. J Virol 2013 Oct;87(19):10515-10523. "Proliferation of naturally EBV-infected gastric carcinoma cells was suppressed by BARF1 siRNA (p < 0.05). Immunohistochemical analysis of 120 human gastric carcinoma tissues demonstrated increased expression of cyclin D1 and reduced expression of p21WAF1 in EBV-positive samples versus EBV-negative gastric carcinomas (p < 0.05)."

Chang - J Virol 2013 abstract / PubMed

DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus. K Matsusaka, S Funata, M Fukayama, A Kaneda. World J Gastroenterol 2014 Apr 14;20(14):3916-3926. Review.

Matsusaka - World J Gastroenterol 2014 full article / PubMed Central
Matsusaka / World J Gastroenterol 2014 full article

Integrative Identification of Epstein-Barr Virus-associated Mutations and Epigenetic Alterations in Gastric Cancer. Q Liang, X Yao, S Tang, J Zhang, TO Yau, X Li, CM Tang, W Kang, RW Lung, JW Li, TF Chan, R Xing, Y Lu, KW Lo, N Wong, KF To, C Yu, FK Chan, JJ Sung, J Yu. Gastroenterology 2014 Dec;147(6):1350-1362.e4. "[I]nfected cells expressed 9 EBV genes previously detected in EBV-associated gastric tumors and 71 EBV genes not previously reported in gastric tumors. Ten viral genes that had not been previously reported in gastric cancer but were most highly expressed in EBV-infected cells were also expressed in primary EBV-positive gastric tumors. Whole-genome sequence analysis identified 45 EBV-associated non-synonymous mutations. These mutations, in genes such as AKT2, CCNA1, MAP3K4, and TGFBR1, were significantly associated with EBV-positive gastric tumors, compared with EBV-negative tumors. An activating mutation in AKT2 was associated with reduced survival times of patients with EBV-positive gastric cancer (P=.006); this mutation was found to dysregulate MAPK signaling. Integrated epigenome and transcriptome analyses identified 216 genes transcriptionally downregulated by EBV-associated hypermethylation; methylation of ACSS1, FAM3B, IHH, and TRABD increased significantly in EBV-positive tumors. Overexpression of IHH and TRABD increased proliferation and colony formation of gastric cancer cells, whereas knockdown of these genes reduced these activities. We found 5 signaling pathways (axon guidance, focal adhesion formation, interactions among cytokines and receptors, MAPK signaling, and actin cytoskeleton regulation) to be commonly affected by EBV-associated genomic and epigenomic alterations."

Liang - Gastroenterology 2014 abstract / PubMed

Epstein-Barr Virus-Associated Gastric Carcinoma: Use of Host Cell Machineries and Somatic Gene Mutations. H Abe, A Kaneda, M Fukayama. Pathobiology 2015 Aug 25;82(5):212-223. "EBV uses various host-cell machineries, including cell division machinery to propagate clonal virus genomes, DNA-methylation machinery to epigenetically control infected cells, and microRNA and exosome machineries to modify the behavior and microenvironment of infected cells. Recent comprehensive molecular analyses from The Cancer Genome Atlas project demonstrate that EBVaGC is a representative molecular subtype that is distinct from microsatellite unstable, genomically stable and chromosome unstable subtypes. In addition to having the highest level of DNA methylation in CpG islands of promoter regions, EBVaGC harbors particular gene alterations, including a high frequency of mutations in PIK3CA and ARID1A, mutation in BCOR, and amplification of PD-L1 and PD-L2."

Abe - Pathobiology 2015 abstract / PubMed

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

Host Gene Expression Is Regulated by Two Types of Noncoding RNAs Transcribed from the Epstein-Barr Virus BamHI A Rightward Transcript Region. AR Marquitz, A Mathur, RH Edwards, N Raab-Traub. J Virol 2015 Nov 15;89(22):11256-11268. In the AGS gastric cancer cell line, myc was activated by BART expression alone. "These transcriptional changes significantly overlapped the transcriptional changes induced during latent EBV infection of these same cells, where the BARTs are exclusively nuclear and do not encode proteins."

Marquitz - J Virol 2015 abstract / PubMed

Host SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be downregulated by Epstein-Barr virus. P Saju, N Murata-Kamiya, T Hayashi, Y Senda, L Nagase, S Noda, K Matsusaka, S Funata, A Kunita, M Urabe, Y Seto, M Fukayama. Nat Microbiol 2016 Mar 14;1:16026. "In vitro infection of gastric epithelial cells with EBV induces SHP1 promoter hypermethylation, which strengthens phosphorylation-dependent CagA action via epigenetic downregulation of SHP1 expression. Clinical specimens of EBV-positive gastric cancers also exhibit SHP1 hypermethylation with reduced SHP1 expression."

Saju - Nat Microbiol 2016 abstract / PubMed

The biological properties of different Epstein-Barr virus strains explain their association with various types of cancers. MH Tsai, X Lin, A Shumilov, K Bernhardt, R Feederle, R Poirey, A Kopp-Schneider, B Pereira, R Almeida, HJ Delecluse. Oncotarget 2017 Feb 7;8(6):10238-10254. Comparison of gastric carcinoma strains SNU719, GP202, and YCCEL1, NPC strain M81, and several laboratory strains of EBV. YCCEL1 and M81 infected primary epithelial cells, gastric carcinoma cells and gastric spheroids more efficiently than Akata or B95-8.

Tsai - Oncotarget 2017 abstract / PubMed
Tsai / Oncotarget 2017 full article

The Phylogeographic Diversity of EBV and Admixed Ancestry in the Americas⁻Another Model of Disrupted Human-Pathogen Co-Evolution. AH Corvalán, J Ruedlinger, T de Mayo, I Polakovicova, P Gonzalez-Hormazabal, F Aguayo. Cancers (Basel) 2019 Feb 14;11(2). Review. "This observation proposes that a 'disrupted co-evolution' might explain the high prevalence of EBV-associated GC in the Americas."

Corvalán / Cancers (Basel) 2019 full article

Molecular and pathological features in patients with gastric cancer in Argentina. Association between Epstein Barr Virus, MSI, PD-L1 expression and T-cells infiltration. M Kujaruk, R Salanova, G Ruiz, M Rizzolo, M Golubicki, G Mendez. Ann Oncol 2019 Jul;30 Suppl 4:iv85. 47 patients. "Qualitative PCR for EVB was positive in 21% (n = 10) of cases."

Kujaruk / Ann Oncol 2019 full article

A possible role for JC virus

Oncogenic T-antigen of JC virus is present frequently in human gastric cancers. SK Shin, MS Li, F Fuerst, E Hotchkiss, R Meyer, T Kim 2nd, A Goel, CR Boland. Cancer 2006 Aug 1;107(3):481-488. "Twenty-one of 37 gastric cancers (57%) harbored JCV T-Ag sequences, and 13 of 37 gastric cancers (30%) contained VP-1 sequences. T-Ag sequences also were found in adjacent nonneoplastic mucosa. In addition, JCV regulatory region sequences were present frequently in gastric cancers and adjacent nonneoplastic mucosa. T-Ag protein expression was found in 9 of 23 gastric cancers (39%), whereas no expression was observed in any of the nonneoplastic tissues."

Shin - Cancer 2006 abstract / PubMed

High JC virus load in gastric cancer and adjacent non-cancerous mucosa. Y Murai, HC Zheng, HO Abdel Aziz, H Mei, T Kutsuna, Y Nakanishi, K Tsuneyama, Y Takano. Cancer Sci 2007 Jan;98(1):25-31. "Twenty-two sample pairs of fresh tumor and adjacent non-cancerous tissue (ANCT) as well as 10 normal gastric mucosa specimens were investigated on the basis of nested polymerase chain reaction (PCR) followed by Southern blotting, DNA direct sequencing, real-time PCR, in situ PCR and immunohistochemistry. The T antigen sequence was detected in 86.4% of gastric cancers and ANCT, and in 100% of the normal mucosa samples, as for virus capsid protein, 54.1%, 68.1% and 70%, respectively. A generally low incidence was noted for agnoprotein. The JCV DNA load was approximately 10-fold higher in both gastric cancers and paired ANCT (4784 +/- 759 and 5394 +/- 1466 copies/microg DNA, respectively) than in normal gastric tissue (542.4 +/- 476.0 copies/microg DNA, P < 0.0001). In situ PCR revealed sporadic JCV genome-positive cancer cells and foveolar epithelial cells. T antigen protein expression assessed by immunohistochemistry was detected only in one case (1/22; 4.5%), probably because the half life of T antigen might be short."

Murai - Cancer Sci 2007 abstract / PubMed

JC [corrected] virus detection in human tissue specimens. H Zheng, Y Murai, M Hong, Y Nakanishi, K Nomoto, S Masuda, K Tsuneyama, Y Takano. J Clin Pathol 2007 Jul;60(7):787-793. Figure 3 Jamestown Canyon virus (JCV) loads in gastric samples: JCV copies/µg were lower in paraffin-embedded samples than in samples that were frozen, <1000 vs approx. 5000, p<0.001; and were lower in 10 normal gastric mucosa samples than in 20 gastric carcinomas, <1000 vs approx. 5000, p<0.001.

Zheng - J Clin Pathol 2007 abstract / PubMed
Zheng / J Clin Pathol 2007 full article

Genetic and epigenetic characteristics of gastric cancers with JC virus T-antigen. S Yamaoka, H Yamamoto, K Nosho, H Taniguchi, Y Adachi, S Sasaki, Y Arimura, K Imai, Y Shinomura. World J Gastroenterol 2009 Nov 28;15(44):5579-5585. "JCV T-Ag protein expression was found in 49% of 90 gastric cancer tissues. T-Ag positivity was not correlated with clinicopathological characteristics. T-Ag expression was detected in a similar percentage of EBV positive cancers (4 of 9, 44%) and EBV negative cancers (35 of 73, 48%). T-Ag expression was detected in a significantly lower percentage of MSI-H cancers (14%) than in non MSI-H cancers (55%, P = 0.005). T-Ag expression was detected in a significantly higher percentage of cancers with nuclear/cytoplasmic localization of beta-catenin (15 of 21, 71%) than in cancers without (42%, P = 0.018). p53 mutations were detected in a significantly lower percentage of T-Ag positive cancers (32%) than in T-Ag negative cancers (57%, P = 0.018). T-Ag positive gastric cancers showed a significant increase in the allelic losses and aberrant methylation compared with T-Ag negative gastric cancers (P = 0.008 and P = 0.003)."

Yamaoka - World J Gastroenterol 2009 full article / PubMed Central

The presence of JC virus in gastric carcinomas correlates with patient's age, intestinal histological type and aberrant methylation of tumor suppressor genes. F Ksiaa, S Ziadi, M Mokni, S Korbi, M Trimeche. Mod Pathol 2010 Apr;23(4):522-530. 61 cases of primary gastric carcinomas and in 53 paired non-tumor gastric mucosa by PCR. "JCV T-antigen sequence was more frequently detected in gastric carcinomas than in non-tumor gastric mucosa (26 vs 6%, P=0.03), while those of SV40 and BKV were not detected in any cases. Correlation analysis showed that JCV had higher frequency in patients older than 55 years (P=0.034) and in the intestinal histological type (P=0.04). With regard to methylation status, P16 and P14 showed significantly higher methylation frequencies in JCV-positive gastric carcinomas than in JCV-negative cases (P=0.007 and P=0.003, respectively). Moreover, the mean of the methylation index was significantly higher in JCV-positive than in JCV-negative cases (P=0.024)."

Ksiaa - Mod Pathol 2010 abstract / PubMed

See also:

Helicobacter pylori causes ulcers and stomach cancer
EBV & Socioeconomic Status
Confounding By Infection
JC Polyoma Virus Causes Colon Cancer

Epstein-Barr Virus Causes Nasopharyngeal Cancer
Epstein-Barr Virus Causes Lymphomas
EBV Causes Lymphoepithelioma-like Lung Cancer
EBV Causes Interstitial Lung Disease
EBV and Other Diseases
EBV Causes Multiple Sclerosis
Epstein-Barr Virus Causes Sjogren’s Syndrome
EBV Causes Lupus


cast 05-11-20