title: Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy.
abstract: Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC - high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV.
authors.affiliation: Department of Pathology, Tulane University, New Orleans, Louisiana, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Strong
authors.forename: Guorong
authors.initials: G
authors.lastname: Xu
authors.forename: Joseph
authors.initials: J
authors.lastname: Coco
authors.forename: Carl
authors.initials: C
authors.lastname: Baribault
authors.forename: Dass S
authors.initials: DS
authors.lastname: Vinay
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Lacey
authors.forename: Amy L
authors.initials: AL
authors.lastname: Strong
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Lehman
authors.forename: Michael B
authors.initials: MB
authors.lastname: Seddon
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lin
authors.forename: Monica
authors.initials: M
authors.lastname: Concha
authors.forename: Melody
authors.initials: M
authors.lastname: Baddoo
authors.forename: Marybeth
authors.initials: M
authors.lastname: Ferris
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Swan
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Sullivan
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Taylor
authors.forename: Erik K
authors.initials: EK
authors.lastname: Flemington
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D030561:Databases, Nucleic Acid; D020031:Epstein-Barr Virus Infections / Q000453:epidemiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000235:genetics / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D012367:RNA, Viral; D014764:Viral Proteins