A protein and mRNA expression-based classification of gastric cancer

Abstract

The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques. Gastric carcinoma is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Despite better control over known risk factors and development of new chemotherapeutic and targeted agents, in the United States, the 5-year overall survival for gastric cancer patients is only 29%. 1 With regard to patient stratification, although several morphologic classifications have been developed, one broadly used system is the Lauren classification, which divides gastric adenocarcinoma into intestinal and diffuse types. 2 The simple two-tiered classification gives a general understanding of the histogenesis and biology of gastric cancer, and has been particularly helpful in evaluating the epidemiologic data. Another widely used system is the WHO classification, which is based on more precise histologic patterns. It is an all-inclusive system, which recognizes all the rare subtypes that were not identified in the Lauren classification. 3 Nevertheless, its clinical utility is doubtful as there is little difference in outcomes between the distinct histological subgroups.Following the successful Trastuzumab for Gastric Cancer (ToGA) trial, the only validated predictive biomarker for personalized therapy of gastric cancer is limited to human epidermal growth factor receptor (Her2) protein expression. 4 Recently, anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody (ramucirumab) has been FDA approved, and anti-epidermal growth factor receptor (EGFR) an...

Immunohistochemistry as a surrogate for molecular subtyping of gastric adenocarcinoma

“…their tumors into more than four groups [24,25]. This approach expands on that of TCGA and similarly may have future therapeutic and prognostic implications.…”

Chromosomal Instability in Gastric Cancer Biology

“…The APC (adenomatous polyposis coli) is a tumor suppressor gene coding for a regulator of the Wnt pathway and has many tasks like labeling β-catenin for degradation [62]. Loss of the C terminus of APC can induce CIN in CRC, making it a prominent factor involved in chromosomal stability [63]. Dunican et al reported that PLK, CCNA2 , and RanBP2 are overexpressed in CIN-type CRC and claimed them to be a tool for separating CIN-type from MSI-type cancers [64].…”

“…It was suggested that p53 aberrant GCs incline toward higher HER2/neu expression, and the potential targeting molecules can be HER2, EGFR, VEGFR, MET, FGFR2, and cell cycle mediators (CCNE1, CCND1, and CDK6), which were all overexpressed. Oppositely, the p53 normal group had a high MUC6 expression and had been defined as the subtype with expression of normal gastric mucosa genes [63].…”

Clinicopathologic implications of immune classification by PD-L1 expression and CD8-positive tumor-infiltrating lymphocytes in stage II and III gastric cancer patients

“…However, other GCs are heterogeneous. Recent studies have proposed that additional markers, including epithelial-mesenchymal transition (EMT) features and TP53 mutations, could be used for further molecular classification [17, 18], although little is known about these categories from a tumor microenvironment-related perspective.…”