title: Deregulation of immune response genes in patients with Epstein-Barr virus-associated gastric cancer and outcomes.
abstract: OBJECTIVE
  Patients with Epstein-Barr virus-associated gastric carcinoma (EBVaGC) have a better prognosis than those with gastric cancer not associated with EBV infection (EBVnGC). This is partly because EBV infection recruits lymphocytes, which infiltrate the tumor. A high degree of tumor heterogeneity is likely to be associated with poor response. We investigated differences in gene expression patterns between EBVaGC and EBVnGC.
  
  
  METHODS
  We used gene expression profile analysis to compare tumor and nontumor gastric tissues from 12 patients with EBVaGC and 14 patients with EBVnGC. Findings were validated by whole transcriptome RNAseq and real-time quantitative polymerase chain reaction analyses. CD3(+) primary T cells were isolated from human blood samples; migration of these cells and of Jurkat cells were measured in culture with EBV-infected and uninfected gastric cancer cells.
  
  
  RESULTS
  Based on Pearson correlation matrix analysis, EBVaGCs had a higher degree of homogeneity than EBVnGCs. Although 4550 genes were differentially expressed between tumor and nontumor gastric tissues of patients with EBVnGC, only 186 genes were differentially expressed between tumor and nontumor gastric tissues of patients with EBVaGC (P < .001). This finding supports the concept that EBVaGCs have fewer genetic and epigenetic alterations than EBVnGCs. Expression of major histocompatibility complex class II genes and genes that regulate chemokine activity were more often deregulated in EBVaGCs compared with nontumor tissues. In culture, more T cells migrated to EBV-infected gastric cancer cells than to uninfected cells; migration was blocked with a neutralizing antibody against CXCR3 (a receptor for many chemokines).
  
  
  CONCLUSIONS
  Fewer genes are deregulated in EBVaGC than in EBVnGC. Most changes in EBVaGCs occur in immune response genes. These changes might allow EBVaGC to recruit reactive immune cells; this might contribute to the better outcomes of these patients compared with those with EBVnGC.
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology, Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Samsung Biomedical Research Institute, Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Ewha Research Center for Systems Biology, Ewha Womans University, Seoul, Korea.
authors.forename: Charny
authors.initials: C
authors.lastname: Park
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology, Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ha-Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology, Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Samsung Biomedical Research Institute, Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
authors.forename: Jinha
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Department of Biochemistry, Seoul National University College of Medicine, Seoul, Korea; Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Department of Surgery, Center for Gastric Cancer, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Min Gew
authors.initials: MG
authors.lastname: Choi
authors.affiliation: Department of Surgery, Center for Gastric Cancer, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sung
authors.initials: S
authors.lastname: Kim
authors.affiliation: Samsung Biomedical Research Institute, Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: kkmkys@skku.edu.
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology, Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Samsung Biomedical Research Institute, Center for Future Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: mkang@skku.edu.
authors.forename: Myung-Soo
authors.initials: MS
authors.lastname: Kang
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D016022:Case-Control Studies; D002634:Chemotaxis, Leukocyte; D016000:Cluster Analysis; D018920:Coculture Techniques; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000235:genetics* / Q000276:immunology*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D019169:Jurkat Cells; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors / Q000276:immunology; D017423:Sequence Analysis, RNA; D013274:Stomach Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D014407:Tumor Cells, Cultured
chemical_list: D057134:Antibodies, Neutralizing; C515187:CXCR3 protein, human; D012333:RNA, Messenger; D054367:Receptors, CXCR3
keywords: Anti-Tumor Immunity; Stomach Cancer; Survival; Viral Infection