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

Authors and Affiliations:

Irene Gullo^1,2,3,4, Joana Carvalho^3,4, Diana Martins^3,4, Diana Lemos^3,4, Ana Rita Monteiro^3,4, Marta Ferreira^3,4, Kakoli Das⁵, Patrick Tan^5,6,7, Carla Oliveira^3,4, Fátima Carneiro^1,2,3,4, Patrícia Oliveira^3,4

¹ Department of Pathology, Centro Hospitalar de São João, Porto, Portugal

² Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal

³ Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Porto, Portugal

⁴ Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal

⁵ Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore

⁶ Genome Institute of Singapore, Biopolis, Singapore 138672, Singapore

⁷ Cancer Science Institute of Singapore, National University of Singapore

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.

Journal: International Journal of Molecular Science, Volume 19, Issue 7, 2018

Link: https://www.mdpi.com/1422-0067/19/7/2079