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. 2018 Nov;21(6):1064-1070.
doi: 10.1007/s10120-018-0851-9. Epub 2018 Jun 18.

Transcriptional analysis of immune genes in Epstein-Barr virus-associated gastric cancer and association with clinical outcomes

Raghav Sundar  1   2 , Aditi Qamra  2 , Angie Lay Keng Tan  2 , Shenli Zhang  2 , Cedric Chuan Young Ng  3 , Bin Tean Teh  3 , Jeeyun Lee  4 , Kyoung-Mee Kim  5 , Patrick Tan  6   7   8   9
Affiliations

Transcriptional analysis of immune genes in Epstein-Barr virus-associated gastric cancer and association with clinical outcomes

Raghav Sundar et al. Gastric Cancer. 2018 Nov.

Abstract

Background: Epstein-Barr virus-associated gastric cancer (EBVaGC) has traditionally been associated with high expression of PD-L1 and immune infiltration. Correlations between PD-L1 and other immune-related gene (IRG) expressions in EBVaGC have not been previously described.

Methods: We performed NanoString® transcriptomic profiling and PD-L1 immunohistochemistry (IHC) (using the FDA approved Dako PD-L1 IHC 22C3) on EBVaGC samples from gastric cancer patients undergoing primary tumor resections at Samsung Medical Centre, South Korea. For controls, EBV-negative samples from the previously reported Asian Cancer Research Group (EBVnegACRG) cohort were used. Genes tested included PD-L1 and other IRGs related to intra-tumoral cytolytic activity, cytokines and immune checkpoints. Samples with PD-L1 expression > 34th percentile were defined as PD-L1high and the remaining as PD-L1low.

Results: We identified 71 cases of EBVaGC and 193 EBV-negative ACRG samples as controls. EBVaGC showed higher expression of all queried immune genes compared to EBVnegACRG samples (p < 0.01). PD-L1 immunohistochemistry expression correlated with PD-L1 transcript expression (r = 0.63, p < 0.001). Tumor-infiltrating lymphocyte patterns were also found to be different between PD-L1low and PD-L1high groups. PD-L1low EBVaGC samples (n = 24, 34%) had consistently decreased expression of all other immune genes, such as CD8A, GZMA and PRF1 and PD-1 (p < 0.001). PD-L1low EBVaGC samples were also associated with worse disease-free survival (HR 5.03, p = 0.032) compared to PD-L1high EBVaGC samples.

Conclusions: A substantial proportion of EBVaGC does not express high levels of PD-L1 and other immune genes. EBVaGCs which have lower transcriptomic expression of PD-L1 tend to have a similarly low expression of other immune genes, IHC scores and a poorer prognosis.

Keywords: Epstein–Barr virus-associated gastric cancer; Immune genes; PD-L1.

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