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.)

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."

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."

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."

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]

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."

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."

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.

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.

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."

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."

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."

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."

[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."

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...."

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.

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.

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).

[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.

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.

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)."

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%)."

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).

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.

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).

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."

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.

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.

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.

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.

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."

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.

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.

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.

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.

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.

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."

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.

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.

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."

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."

[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).

[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.

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)."

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."

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.

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).

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).

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."

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).

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 [Epub ahead of print]. 9 (3%) were EBV positive, out of 273 formalin fixed paraffin-embedded cases of gastric carcinoma.

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)."

Mechanisms

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."

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."

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."

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."

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."

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."

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."

See also:

cast 03-07-08