HER2–CDH1 Interaction via Wnt/B-Catenin Is Associated with Patients’ Survival in HER2-Positive Metastatic Gastric Adenocarcinoma

SIMPLE SUMMARY: A deeper understanding of the molecular mechanisms involved in gastric cacner (GC) pathologenesis would help the identification of prognostic biomarkers and the development of new treatments. Human epidermal growth factor receptor 2 (HER2/ErbB2), a membrane-bound receptor of the EGFR family, may be overexpressed in GC. Trastuzumab is a HER2 inhibitor used to treat HER2+ metastatic gastric cancer (mGC). The present study aims to investigate the relationship between CDH1 mRNA expression and HER2-positivity in mGC using a multiplexed gene expression profile in two series of GC patients: 38 HER2+ and HER2- mGC and 36 HER2- GC with and without metastasis. Our results revealed the relationship between CDH1 and HER2 mRNA expression in mGC via the canonical WNT/β-catenin pathway and identified EGF as an independent prognostic biomarker for survival. ABSTRACT: Trastuzumab is a human epidermal growth factor receptor 2 (HER2) inhibitor used to treat HER2+ metastatic gastric cancer (mGC). The present study aims to investigate the relationship between CDH1 mRNA expression and HER2-positivity in mGC using a multiplexed gene expression profile in two series of gastric cancer (GC): Series 1 (n = 38): HER2+ and HER2- mGC; Series 2 (n = 36) HER2- GC with and without metastasis. To confirm the results, the same expression profiles were analyzed in 354 GC from The Cancer Genome Atlas (TCGA) dataset. The difference in gene expression connected HER2 overexpression with canonical wingless-type (Wnt)/β-catenin pathway and immunohistochemical (IHC) expression loss of E-cadherin (E-CAD). CDH1 mRNA expression was simultaneously associated with the rs16260-A variant and an increase in E-CAD expression. Differences in retinoic acid receptor alfa (RARA), RPL19 (coding for the 60S ribosomal L19 protein), catenin delta 1 (CTNND1), and epidermal growth factor (EGF) mRNA levels—all included in the Wnt/β-catenin pathway—were found associated with overall survival (OS). RARA, CTNND1, and EGF resulted in independent OS prognostic factors. EGF was confirmed as an independent factor along with TNM stage in HER2-overpressed mGC from TCGA collection. Our study highlighted factors involved in the WNT/β-catenin pathway that interconnected E-CAD with HER2 overexpression and patient survival.