Epstein-Barr Virus-Associated Gastric Carcinoma: Use of Host Cell Machineries and Somatic Gene Mutations

Abstract

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct subtype of gastric carcinoma, consisting of clonal growth of EBV-infected epithelial cells. Its unique characteristics have been demonstrated by epidemiological, clinical and pathological studies using in situ hybridization for EBV-encoded small RNAs. An oncogenic process for EBVaGC has also been revealed. 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. Although currently undetermined, the virus might use the altered cellular functions that are induced by these somatic mutations. Further investigation of virus-driven oncogenesis will enable hitherto unknown functions of stomach epithelial cell machineries to be elucidated, which may reveal potential therapeutic targets for EBVaGC.

Status of Epstein-Barr Virus Coinfection withHelicobacter pyloriin Gastric Cancer

“…Promoter region hypermethylation in certain genes is frequently seen in EBV-positive GC compared to EBV-negative GC [16, 186]. GC and other most common cancers occur by the genetic and epigenetic changes over an extended period.…”

Molecular Pathogenesis of Gastric Adenocarcinoma

“…EBVaGC occurs in the upper and middle stomach in the majority. Fukayama et al indicated the tumor distribution in the stomach, with the proportion that 58% in the cardia, 33% in the body, and 9% in the antrum [20,21]. They also depicted the appearance of EBVaGC as ulcerated or saucer-like, with obvious thickened gastric wall.…”

Virus de Epstein-Barr y su relación con el desarrollo del cáncer

“…Recientemente, dados los soportes de la asociación VEB-CG, la nueva clasificación molecular del CG incluye un subtipo denominado CaGVEB (76), del cual se conocen dos tipos histológicos: el carcinoma gás-trico similar al linfoepitelioma o carcinoma gástrico con estroma linfoide (85 % a 95 % de los casos) y el adenocarcinoma (5 % a 15 % de los casos) (77)(78)(79). Se sabe que el CaGVEB se presenta en 2 % a 20 % de la población mundial.…”

“…Se sabe que el CaGVEB se presenta en 2 % a 20 % de la población mundial. Anualmente se diagnostican de 200 000 a 876 000 casos nuevos de CaGVEB, que causan 69 081 a 90 000 muertes cada año (77,(80)(81)(82)(83). En Colombia, la tasa más alta de mortalidad por CaGVEB se reporta en regiones montañosas y la más baja, en regiones planas; es más frecuente en hombres jóvenes y el subtipo histológico predominante es el adenocarcinoma de tipo difuso (84).…”