Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy

Abstract

Gastric cancer (GC) is a leading cause of death. We aim to establish a clinically relevant assay that encompasses recent molecular classifications and provides useful clinical information in a large cohort of GC patients. A consecutive series of 438 GC patients that underwent palliative chemotherapy between 2014 and 2015 were assessed using 10 GC panels: EBER in-situ hybridization, immunohistochemistry for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), receptor tyrosine kinases (RTKs; HER2, EGFR, and MET), PTEN, and p53 protein. With a median of one aberration, 3.3 % of samples analyzed were Epstein-Barr virus (EBV)-positive; 4.8%, MMR-deficient. RTKs were overexpressed in 218 patients; EGFR was most commonly overexpressed (39.9%), followed by HER2 (13.5%) and MET (12.1%). Furthermore, 2.5 % and 10.7 % of cases had simultaneous overexpression of three and two RTKs, respectively. p53 overexpression/null tumors were identified in 259 patients (59.1%), and PTEN loss was identified in 89 patients (20.3%). EBV-positivity was mutually exclusive with MMR-deficiency, predominantly identified in male patients, and these tumors were undifferentiated with proximal location. p53 mutant type was significantly found predominantly in the EBV-negative (60.6% vs 14.3%, P=0.001) and HER2-positive (78.0% vs 56.2%, P=0.002) groups. We described a molecular spectrum of distinct GC subtypes using clinically applicable assay. This assay will provide a convenient screening tool and facilitate the development of targeted agents in clinical trials.

Clinicopathological and prognostic features of Epstein‐Barr virus infection, microsatellite instability, and PD‐L1 expression in gastric cancer

“…In this research, 10.5% of patients were EBV‐positive and 27% had MSI, which is comparable to the rates seen in TCGA, (9% and 22% of GCs, respectively) . The simultaneous loss of MLH1 and PMS2 expression was the most common type of instability (60% in our study), as also described by Kim et al in 71.4% of their MSI GC cases.…”

“…15 In this research, 10.5% of patients were EBV-positive and 27% had MSI, which is comparable to the rates seen in TCGA, (9% and 22% of GCs, respectively). 4 The simultaneous loss of MLH1 and PMS2 expression was the most common type of instability (60% in our study), as also described by Kim et al 16 PD-L1 is a transmembrane surface glycoprotein encoded by the CD274 gene expressed by several cell types of the immune system (as lymphocytes and dendritic cells), but can also be expressed in tumor cells. Although PD-L1 has been reported in several solid tumors, only few studies investigated its expression in GC.…”

Gastric cancer: Basic aspects

“…The GC group with normal p53 *Molina-Castro and Pereira-Marques are contributed equally to the work. expression were most frequently intestinal type and had increased MUC6 expression, and authors suggest that these features likely correspond to the metabolic subtype reported by Lei et al 2 Kim et al 9 undertook a similar approach to analyze the expression of 10 molecular markers in a consecutive series of 438 advanced (metastatic) GCs from Korea. In addition to EBV EBER, MMR proteins, and p53, they have also analyzed the expression of receptor tyrosine kinases HER2, EGFR, and MET.…”

“…Kim et al . undertook a similar approach to analyze the expression of 10 molecular markers in a consecutive series of 438 advanced (metastatic) GCs from Korea.…”

Enrichment of CLDN18‐ARHGAP fusion gene in gastric cancers in young adults

“…20 Two lines of observation support the idea that GCYAs have a different group of etiologies from EBV and MSI GC subtypes. First, EBV-positive tumors are often biased to men, 19,39,41 and MSI-positive GC typically affects elders. 19 Second, longstanding accumulation of DNA methylations are thought to underlie MSI tumors, suppressing the expression of gene sets including MLH1.…”