Chun-kui Shao

Epstein-Barr virus-associated gastric carcinoma: a newly defined entity.

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a recently recognized entity, which is defined by the presence of EBV in the gastric carcinoma cells. EBVaGC represents about 10% of gastric carcinoma worldwide, and >80,000 patients are estimated to develop EBVaGC annually. EBVaGC shows some distinct clinicopathologic characteristics, such as male predominance, predisposition to the proximal stomach, and a high proportion in diffuse-type gastric carcinomas. Besides, EBVaGC also shows characteristic molecular abnormality, that is, global and nonrandom CpG-island methylation of the promoter region of many cancer-related genes, which causes downregulation of their expression. Moreover, EBVaGC has a relative favorable prognosis. The uniform presence of EBV-encoded small RNA in tumor cells but not in the surrounding normal epithelial cells, and the detection of monoclonal EBV episomes in EBVaGC, strongly suggests that EBV play an etiological role in gastric carcinogenesis. Therefore, EBVaGC should be regarded as a distinct entity of gastric carcinoma, although it only accounts for a relatively small fraction of total gastric carcinomas. In this review, the epidemiological and clinicopathologic features of EBVaGC and the genetic abnormalities of EBVaGC cell including chromosomal and epigenetic abnormalities are described. The roles of EBV in gastric carcinogenesis are discussed. We make an emphasis on the EBV latency pattern and genome polymorphisms as well as local immunity in EBVaGC. In addition, the treatment of EBVaGC is also briefly discussed. Taken together, this review aims to give the reader a full understanding of a newly defined entity of gastric carcinoma, EBVaGC.

Association of distinctive Epstein–Barr virus variants with gastric carcinoma in Guangzhou, southern China†

To investigate the clinicopathologic features, Epstein–Barr virus (EBV) latency pattern and genome polymorphism of EBV‐associated gastric carcinoma (EBVaGC) in Guangzhou, an endemic area of nasopharyngeal carcinoma (NPC), an in situ hybridization assay of EBV‐encoded small RNA‐1 (EBER‐1) was used to identify the presence of EBV in 676 consecutive gastric carcinoma cases. EBV‐encoded proteins EBNA1, EBNA2, LMP1, and ZEBRA were detected by immunohistochemistry. EBV genome polymorphism was also analyzed by PCR and DNA sequencing. Of the 676 cases, 45 EBV‐positive cases (6.7%) were identified, including 37 (8.5%) male and 8 (3.3%) female cases. EBNA1 was detected in 42 cases (93.3%), while EBNA2, LMP1, and ZEBRA were all negative. 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. J. Med. Virol. 82:658–667, 2010.

Epstein-Barr virus genome polymorphisms of Epstein-Barr virus-associated gastric carcinoma in gastric remnant carcinoma in Guangzhou, southern China, an endemic area of nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) is associated with a subset of gastric carcinoma which was defined as EBV-associated gastric carcinoma (EBVaGC). The proportion of EBVaGC in gastric remnant carcinoma (GRC) was apparently higher than that in conventional gastric carcinoma (CGC) which occurs in the intact stomach. To clarify the possible mechanisms, 26 GRC cases from Guangzhou were investigated for the presence of EBV, and the EBV genome polymorphisms of EBVaGC in GRC were analyzed. Besides, the clinicopathologic characteristics, EBV latency pattern of EBVaGC in GRC were also investigated. Eight (30.8%) out of 26 cases were identified as EBVaGCs. Type A strain, prototype F, type I, mut-W1/I1, XhoI- and del-LMP1 variants were predominant among EBVaGC patients, accounting for 7 (87.5%), 7 (87.5%), 8 (100%), 6 (75%), 5 (62.5%) and 8 (100%) cases, respectively. All EBVaGC cases were male and with the histology of diffuse-type carcinoma. The tumor cells expressed EBNA1 (87.5%) and LMP2A (62.5%) but not LMP1, EBNA2 and ZEBRA. Thus, the EBV latency pattern was latency I. These were similar to those in CGC, except for the significantly higher proportion of EBVaGC in GRC than in CGC, suggesting that there is no more aggressive EBV variant in EBVaGC in GRC, and the injuries of gastric mucosa and/or changes of the microenvironment within the remnant stomach may be involved in the development of EBVaGC in GRC. This, to our knowledge, is the first study concerning about the EBV genome polymorphisms of EBVaGC in GRC in the world.

Expression and prognostic roles of PIK3CA, JAK2, PD-L1, and PD-L2 in Epstein-Barr virus–associated gastric carcinoma

As a special subtype of gastric carcinoma, Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) has distinct clinicopathological features. The Cancer Genome Atlas Research Network revealed that EBVaGC also has distinct molecular features: PIK3CA mutations, DNA hypermethylation, and JAK2, PD-L1, and PD-L2 amplification. Here, we evaluated PIK3CA, JAK2, PD-L1, and PD-L2 expression in 59 EBVaGC and 796 EBV-negative gastric carcinoma (EBVnGC) cases using immunohistochemistry and found that PIK3CA, JAK2, PD-L1, and PD-L2 were highly expressed in 75.9% and 48.8% (P<.001), 81.8% and 71.1% (P=.091), 92.5% and 84.8% (P=.132), and 98.1% and 89.7% (P=.049) of the EBVaGC and EBVnGC cases, respectively. However, the expression of PIK3CA, JAK2, PD-L1, or PD-L2 was not significantly associated with clinicopathological features or patient outcomes in EBVaGC. In contrast, in EBVnGC, high PIK3CA expression was significantly associated with indolent clinicopathological features and independently predicted better 5-year overall survival (57.8% versus 33.4%, P<.001). Our study indicated that the protein expression of the 4 characteristic molecules of EBVaGC was basically consistent with their genetic alterations, making them potential characteristic protein biomarkers and therapeutic targets of EBVaGC. The favorable impact of PIK3CA overexpression on survival found in this study gives us new insight into the clinical significance of PIK3CA in EBVnGC.

Expressions of Osteopontin (OPN), ανβ3 and Pim-1 Associated with Poor Prognosis in Non-small Cell Lung Cancer (NSCLC)

ObjectiveTo examine the expressions of osteopontin (OPN),

Accumulation Mechanisms of CD4 + CD25 + FOXP3 + Regulatory T Cells in EBV-associated Gastric Carcinoma

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Variations of Epstein-Barr virus nuclear antigen 1 in Epstein-Barr virus-associated gastric carcinomas from Guangzhou, southern China.

and Pim-1 in non-small cell lung cancer (NSCLC), and investigate their potential pathogenic roles in the development of NSCLC.MethodsImmunohistochemistry was used to examine the expressions of OPN,