The transcriptomic landscape of gastric cancer: Insights into epstein-barr virus infected and microsatellite unstable tumors
Gullo, I Carvalho, J Martins, D Lemos, D Monteiro, A.R Ferreira, M Das, K Tan, P Oliveira, C Carneiro, F
Gullo, I
Carvalho, J
Martins, D
Lemos, D
Monteiro, A.R
Ferreira, M
Oliveira, C
Carneiro, F
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Alternative Title
Abstract
Background: Epstein-Barr Virus (EBV) positive and microsatellite unstable (MSI-high) gastric cancer (GC) are molecular subgroups with distinctive molecular profiles. We explored the transcriptomic differences between EBV+ and MSI-high GCs, and the expression of current GC immunotherapy targets such as PD-1, PD-L1, CTLA4 and Dies1/VISTA. Methods: Using Nanostring Technology and comparative bioinformatics, we analyzed the expression of 499 genes in 46 GCs, classified either as EBV positive (EBER in situ hybridization) or MSI-high (PCR/fragment analysis). PD-L1 protein expression was assessed by immunohistochemistry. Results: From the 46 GCs, 27 tested MSI-high/EBV?, 15 tested MSS/EBV+ and four tested MSS/EBV?. The Nanostring CodeSet could segregate GCs according to MSI and, to a lesser extent, EBV status. Functional annotation of differentially expressed genes associated MSI-high/EBV? GCs with mitotic activity and MSS/EBV+ GCs with immune response. PD-L1 protein expression, evaluated in stromal immune cells, was lower in MSI-high/EBV? GCs. High mRNA expression of PD-1, CTLA4 and Dies1/VISTA and distinctive PD-1/PD-L1 co-expression patterns (PD-1high/PD-L1low, PD-1high/PDL1high) were associated with MSS/EBV+ molecular subtype and gastric cancer with lymphoid stroma (GCLS) morphological features. Conclusions: EBV+ and MSI-high GCs present distinct transcriptomic profiles. GCLS/EBV+ cases frequently present co-expression of multiple immunotherapy targets, a finding with putative therapeutic implications. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
cytotoxic T lymphocyte antigen 4, messenger RNA, programmed death 1 ligand 1, programmed death 1 receptor, protein, protein Dies1, protein VISTA, unclassified drug, CD274 protein, human, programmed death 1 ligand 1, transcriptome, Article, bioinformatics, cancer immunotherapy, clinical article, correlation analysis, Epstein Barr virus, Epstein Barr virus infection, female, gene expression, human, human tissue, immune response, immunocompetent cell, immunohistochemistry, male, microsatellite instability, mitosis rate, molecular genetics, phenotype, protein expression, software, stomach cancer, stomach tumor, stroma cell, transcriptomics, cluster analysis, Epstein Barr virus, Epstein Barr virus infection, gene expression profiling, gene expression regulation, gene ontology, genetics, metabolism, physiology, procedures, retrospective study, virology, B7-H1 Antigen, Cluster Analysis, Epstein-Barr Virus Infections, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Ontology, Herpesvirus 4, Human, Humans, Microsatellite Instability, Retrospective Studies, Stomach Neoplasms, Transcriptome
Source Title
International Journal of Molecular Sciences
Publisher
MDPI
Series/Report No.
Collections
Rights
Attribution 4.0 International
Date
2018
DOI
10.3390/ijms19072079
Type
Article