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Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy.

Strong MJ, Xu G, Coco J, Baribault C, Vinay DS, Lacey MR, Strong AL, Lehman TA, Seddon MB, Lin Z, Concha M, Baddoo M, Ferris M, Swan KF, Sullivan DE, Burow ME, Taylor CM, Flemington EK - PLoS Pathog. (2013)

Bottom Line: Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC).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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Tulane University, New Orleans, Louisiana, United States of America.

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.

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Related in: MedlinePlus

High numbers of infiltrating immune cellular genes are detected in EBVaGC.(A) Significant immunologically related genes differentially expressed in EBVaGC are represented in a heat map. The log2 fold change intensities are represented by the color gradient with red corresponding to the highest intensity and green corresponding to the lowest. (B) Interferon-gamma (IFNG) associated genes differentially expressed in EBVaGC are displayed in a diagram.
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ppat-1003341-g008: High numbers of infiltrating immune cellular genes are detected in EBVaGC.(A) Significant immunologically related genes differentially expressed in EBVaGC are represented in a heat map. The log2 fold change intensities are represented by the color gradient with red corresponding to the highest intensity and green corresponding to the lowest. (B) Interferon-gamma (IFNG) associated genes differentially expressed in EBVaGC are displayed in a diagram.

Mentions: Ingenuity Pathway Analysis software (IPA: Ingenuity Systems) was used to assist the analysis of pathways and known molecular functions associated with differentially expressed genes. Twenty four percent (116) of the 490 genes with statistically significant differential expression were found to be immunologically related genes (Figure 8A). The vast majority of these genes were expressed at higher levels in hiEBVaGCs with IDO1 and IFNG ranking among the top (38-fold and 16-fold, high v. negative). The differentiation and other cell surface marker profiles are consistent with the presence of cytotoxic T-cells (CTLs) and/or natural killer (NK) cells in hiEBVaGC. Further, CTLs and NK cells are key producers of granzymes and perforin, which are found to be elevated in the hiEBVaGC (Figure 8A).


Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy.

Strong MJ, Xu G, Coco J, Baribault C, Vinay DS, Lacey MR, Strong AL, Lehman TA, Seddon MB, Lin Z, Concha M, Baddoo M, Ferris M, Swan KF, Sullivan DE, Burow ME, Taylor CM, Flemington EK - PLoS Pathog. (2013)

High numbers of infiltrating immune cellular genes are detected in EBVaGC.(A) Significant immunologically related genes differentially expressed in EBVaGC are represented in a heat map. The log2 fold change intensities are represented by the color gradient with red corresponding to the highest intensity and green corresponding to the lowest. (B) Interferon-gamma (IFNG) associated genes differentially expressed in EBVaGC are displayed in a diagram.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3649992&req=5

ppat-1003341-g008: High numbers of infiltrating immune cellular genes are detected in EBVaGC.(A) Significant immunologically related genes differentially expressed in EBVaGC are represented in a heat map. The log2 fold change intensities are represented by the color gradient with red corresponding to the highest intensity and green corresponding to the lowest. (B) Interferon-gamma (IFNG) associated genes differentially expressed in EBVaGC are displayed in a diagram.
Mentions: Ingenuity Pathway Analysis software (IPA: Ingenuity Systems) was used to assist the analysis of pathways and known molecular functions associated with differentially expressed genes. Twenty four percent (116) of the 490 genes with statistically significant differential expression were found to be immunologically related genes (Figure 8A). The vast majority of these genes were expressed at higher levels in hiEBVaGCs with IDO1 and IFNG ranking among the top (38-fold and 16-fold, high v. negative). The differentiation and other cell surface marker profiles are consistent with the presence of cytotoxic T-cells (CTLs) and/or natural killer (NK) cells in hiEBVaGC. Further, CTLs and NK cells are key producers of granzymes and perforin, which are found to be elevated in the hiEBVaGC (Figure 8A).

Bottom Line: Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC).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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Tulane University, New Orleans, Louisiana, United States of America.

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.

Show MeSH
Related in: MedlinePlus