期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 19, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/ijms19072079
关键词
gastric cancer; transcriptomic profiling; Epstein-Barr Virus; EBV; microsatellite instability; MSI
资金
- Fundo Europeu de Desenvolvimento Regional (FEDER) through the Operational Programme for Competitiveness Factors (COMPETE), Norte Portugal Regional Programme-NORTE 2020 (PORTUGAL 2020 Partnership Agreement)
- Portuguese Foundation for Science and Technology (FCT) [DOCnet-NORTE-01-0145-FEDER-000003, NORTE-01-0145-FEDER-000029, GenomePT-POCI-01-0145-FEDER-022184 (ROTEIRO/0044/2013), SFRH/BPD/86543/2012, SFRH/BPD/89764/2012]
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/86543/2012] Funding Source: FCT
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-1(high)/PD-L1(low), PD-1(high)/PDL1(high)) 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.
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