Differences in Gastric Carcinoma Microenvironment Stratify According to EBV Infection Intensity: Implications for Possible Immune Adjuvant Therapy

PLoS Pathogens

Melody Baddoo¹  Monica Concha¹  Carl Baribault²  Joseph Coco²  Michelle R. Lacey³  Michael B. Seddon³  Amy L. Strong⁴  Christopher M. Taylor⁵  Deborah E. Sullivan⁵  MaryBeth Ferris⁵  Michael J. Strong⁵  Teresa A. Lehman⁶  Erik K. Flemington⁶  Guorong Xu⁶  Kenneth F. Swan⁶  Matthew E. Burow⁶  Dass S. Vinay⁶  Zhen Lin⁷ 

[1] BioServe Biotechnologies, Ltd., Beltsville, Maryland, United States of America;Department of Computer Science, University of New Orleans, New Orleans, Louisiana, United States of America;Department of Mathematics, Tulane University, New Orleans, Louisiana, United States of America;Department of Medicine, Section of Clinical Immunology, Allergy, and Rheumatology, Tulane University, New Orleans, Louisiana, United States of America;Department of Pathology, Tulane University, New Orleans, Louisiana, United States of America;Tulane Cancer Center, New Orleans, Louisiana, United States of America;Tulane Center for Stem Cell Research and Regenerative Medicine, New Orleans, Louisiana, United States of America

关键词: Carcinomas;    Gene expression;    RNA sequencing;    Epstein-Barr virus;    Sequence alignment;    Genomic libraries;    RNA sequence analysis;    DNA methylation;   

DOI  :  10.1371/journal.ppat.1003341

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY