Abstract
Simple SummaryA 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.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.
Highlights
IntroductionThe human epidermal growth factor receptor 2 (HER2) functions as a stabilizer of homodimers and heterodimers of ligand bound HER receptor family members, leading to enhancing downstream mitogen and proliferative signals
The human epidermal growth factor receptor 2 (HER2, called ERBB2), is a member of the HER family of tyrosine kinase receptors, which includes EGFR, HER3, and HER4.The HER2 functions as a stabilizer of homodimers and heterodimers of ligand bound HER receptor family members, leading to enhancing downstream mitogen and proliferative signals
EGF, retinoic acid receptor alfa (RARA), RPL19, and catenin delta 1 (CTNND1) mRNA expression that we found involved in the Wnt/β-catenin signature were identified as valuable markers for HER2-positive metastatic gastric cancer (mGC) patient survival
Summary
The HER2 functions as a stabilizer of homodimers and heterodimers of ligand bound HER receptor family members, leading to enhancing downstream mitogen and proliferative signals. The truncated HER2 form, which remains membrane-associated, is found to be 10-to 100-fold more active than the full-length protein HER2. By IHC), account for about 10% to 22% of gastric cancer (GC) and represent a requisite for the addition of trastuzumab (anti-HER2) to first-line chemotherapy in unresectable or metastatic GC (mGC) since its addition increased survival from 11.1 to 13.8 months versus chemotherapy alone [1]. Cadherin 1 (CDH1) gene encodes for E-cadherin (E-CAD), a cell-adhesion molecule involved in maintaining epithelial tissue integrity. A germline pathogenic variant of the CDH1 gene is a distinctive characteristic of hereditary diffuse gastric cancer (HDGC) syndrome. We observed an increased overall survival (OS) in treated HER2-positive mGC patients having the rs16260Ars1801552T CDH1 variants, compared with patients presenting other CDH1 variants [3]
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