Epstein-Barr Virus-Associated Gastric Carcinoma: Use of Host Cell Machineries and Somatic Gene Mutations.
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.
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hiroyuki
H
Abe
Atsushi
A
Kaneda
Masashi
M
Fukayama
D063646:Carcinogenesis; D058534:Class I Phosphatidylinositol 3-Kinases; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D020031:Epstein-Barr Virus Infections / Q000821:virology; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000821:virology*; D014157:Transcription Factors / Q000235:genetics
D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D014157:Transcription Factors; C112476:ARID1A protein, human; C484760:PIK3CA protein, human