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Int. J. Mol. Sci. 2018, 19(7), 2079; https://doi.org/10.3390/ijms19072079

The Transcriptomic Landscape of Gastric Cancer: Insights into Epstein-Barr Virus Infected and Microsatellite Unstable Tumors

1
Department of Pathology, Centro Hospitalar de São João, Porto 4200-319, Portugal
2
Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto 4200-319, Portugal
3
Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Porto 4200-135, Portugal
4
Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto 4200-135, Portugal
5
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore
6
Genome Institute of Singapore, Biopolis, Singapore 138672, Singapore
7
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
*
Author to whom correspondence should be addressed.
Received: 30 May 2018 / Revised: 12 July 2018 / Accepted: 13 July 2018 / Published: 17 July 2018
(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)
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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. View Full-Text
Keywords: gastric cancer; transcriptomic profiling; Epstein-Barr Virus; EBV; microsatellite instability; MSI gastric cancer; transcriptomic profiling; Epstein-Barr Virus; EBV; microsatellite instability; MSI
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Gullo, I.; Carvalho, J.; Martins, D.; Lemos, D.; Monteiro, A.R.; Ferreira, M.; Das, K.; Tan, P.; Oliveira, C.; Carneiro, F.; Oliveira, P. The Transcriptomic Landscape of Gastric Cancer: Insights into Epstein-Barr Virus Infected and Microsatellite Unstable Tumors. Int. J. Mol. Sci. 2018, 19, 2079.

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