Programmed death ligand-1 and MET co-expression is a poor prognostic factor in gastric cancers after resection

Abstract

Programmed death-ligand 1 (PD-L1) plays an essential protein for immune evasion, contributing to tumor development and progression. Recent studies have reported MET as an upregulator for PD-L1 overexpression through an oncogenic pathway. However, an association between PD-L1 expression with MET has not been reported in gastric cancer.The prognostic significance of PD-L1 and its association with Epstein-Barr virus (EBV), microsatellite instability (MSI), and mucin phenotype remain controversial.We performed in situ hybridization for EBV-encoded RNA and immunohistochemistry in tissue microarrays for 394 gastric cancers. A multiplex polymerase chain reaction with five quasimonomorphic markers was performed for MSI.PD-L1 expression was observed in 123 cases (31.2%), and clinicopathological features such as MET overexpression, high pT stage, and a lack of lymphatic invasion represent significant risk factors associated with PD-L1 overexpression in gastric cancers. No associations of EBV, MSI, or mucin phenotype with PD-L1 expression were statistically significant. PD-L1 expression was a strong indicator for worse overall survival (OS) but borderline significant in disease-free survival (DFS). A combined analysis of PD-L1 and MET expression indicated that the PD-L1+/MET+ subgroup showed the worst prognosis when compared to the PD-L1-/MET- subgroup, which had the best clinical outcome. Furthermore, PD-L1 overexpression exhibited poor prognosis in terms of both OS and DFS in EBV-negative, microsatellite stable, and intestinal mucin phenotype tumors. In conclusion, this is the first study to evaluate the overexpression of MET as a risk factor for PD-L1 positivity in gastric cancer tissue as well as the reliability and prognostic relevance of PD-L1/MET co-expression after surgery.

Significance of Druggable Targets (PD-L1, KRAS, BRAF, PIK3CA, MSI, and HPV) on Curatively Resected Esophageal Squamous Cell Carcinoma

“…Consistent with several previous published reports, an IHC score of ≥1+ was considered positive [11,15]. To evaluate the expression of MMR proteins, the following primary antibodies were used in this analysis: anti-MLH1 (pre-diluted; Ventana Medical Systems), anti-MLH2 (1:300; Cell Marque, Rocklin, CA, USA), anti-MSH6 (1:200; Cell Marque), and anti-PMS2 (prediluted; Ventana Medical Systems) antibodies.…”

“…Genomic DNA was extracted from 10-µm thick sections of 10% neutral manually dissected FFPE tumor tissue using the Maxwell ® 16 FFPE Puri cation Kit for DNA (Promega, USA). The mutations in the KRAS (exon 2 and 3), BRAF (exon 14), and PIK3CA (exon 9 and 20) genes were analyzed by directional sequencing of PCR fragments ampli ed from the genomic DNA as previously described [11]. All sequences were con rmed in duplicate for replicate ampli cation reactions.…”

“…The PD-L1/PD-1 axis is reported to be driven by the oncogenic activation of the signaling pathways, such as the mitogen-activated protein kinase (MAPK) and PI3K pathways. Additionally, this axis is regulated by other factors in the tumor microenvironment, including microsatellite instability (MSI) caused by de cient mismatch repair (dMMR) and human papillomavirus (HPV) [8][9][10][11][12]. However, MSI/dMMR, RAS/BRAF/PIK3CA mutations, and HPV status have been rarely investigated in esophageal cancers.…”

A gene expression-based risk model reveals prognosis of gastric cancer

“…In recent decades, molecular biomarkers for gastric prognosis have been widely reported ( Arigami et al, 2013 ; Guo et al, 2013 ; Liu et al, 2015 ; Rachidi et al, 2013 ). PD-L1 and MET1 co-expression predicted a poor survival of gastric cancer, with shorter overall survival rate and disease-free survival rate ( Kwon et al, 2017 ). The low expression of BUB1 also suggested a poor prognosis ( Stahl et al, 2017 ), and EPHB4 showed a similar pattern for prognosis ( Yin et al, 2017 ).…”

Significance of druggable targets (PD-L1, KRAS, BRAF, PIK3CA, MSI, and HPV) on curatively resected esophageal squamous cell carcinoma

“…The PD-L1/PD-1 axis is reported to be driven by the oncogenic activation of the signaling pathways, such as the mitogen-activated protein kinase (MAPK) and PI3K pathways. Additionally, this axis is regulated by other factors in the tumor microenvironment, including microsatellite instability (MSI) caused by de cient mismatch repair (dMMR) and human papillomavirus (HPV) [9][10][11][12][13]. However, MSI/dMMR, RAS/BRAF/PIK3CA mutations, and HPV status have been rarely investigated in esophageal cancers.…”