Characterizing Metastatic HER2-Positive Gastric Cancer at the CDH1 Haplotype

Abstract

The CDH1 gene, coding for the E-cadherin protein, is linked to gastric cancer (GC) susceptibility and tumor invasion. The human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in a portion of GC. HER2 is an established therapeutic target in metastatic GC (mGC). Trastuzumab, in combination with various chemotherapeutic agents, is a standard treatment for these tumors leading to outcome improvement. Unfortunately, the survival benefit is limited to a fraction of patients. The aim of this study was to improve knowledge of the HER2 and the E-cadherin alterations in the context of GC to characterize subtypes of patients that could better benefit from targeted therapy. An association between the P7-CDH1 haplotype, including two polymorphisms (rs16260A-rs1801552T) and a subset of HER2-positive mGC with better prognosis was observed. Results indicated the potential evaluation of CDH1 haplotypes in mGC to stratify patients that will benefit from trastuzumab-based treatments. Moreover, data may have implications to understanding the HER2 and the E-cadherin interactions in vivo and in response to treatments.

Keywords: CDH1; E-cadherin; HER2; metastatic gastric cancer; rs16260; rs1801552.

Figure 1

Schematic diagram of E-cadherin-HER2 interaction. The E-cadherin present three different domains: the conserved cytoplasmic domain, a transmembrane domain, and an extracellular domain. The E-cadherin cytoplasmic tail presents two regions: the catenin-binding domain and the juxtamembrane domain. β-catenin binds to the E-cadherin domain and this complex via α-catenin connects and regulates E-cad interaction with the actin cytoskeleton. p120-catenin binds the CDH1 juxtamembrane domain and stabilizes E-cad expression at the cell surface. (A) Activation of the HER2 by inducing the phosphorylation of β-catenin directs the dissociation of β-catenin from the E-cad complex, thus leading to a decrease of E-cad-mediated cell adhesion, facilitate epithelial-mesenchymal transition (EMT), and the translocation of β-catenin to the nucleus where it acts as a transcriptional regulator of genes involved in cell growth and the EMT process; (B) HER2 activation increases metalloproteinase (MP) activity, which leads to an increased production of soluble E-cadherin (sE-cad) through the cleavage of E-cad. Metalloproteinase also cleaves HER2 into a cytoplasmic tail domain, p95HER2, and a shaded soluble HER2 fragment. The p95HER2 fragment maintains the phosphokinase activity, thus favoring the dissociation of the β-catenin/E-cad complex leading to GC progression and metastasis. The production of the sE-cad causes a reduction in cell adhesion and, by its diffusion into the microenvironment, acts as a paracrine/autocrine signaling molecule that regulates numerous signaling pathways implicated in tumor progression, including a key role in the HER2 interaction/activation and phosphorylation of β-catenin.

Figure 2

Cox regression for overall survival (OS) analysis for the mGC patient subgroup based on the HER2-expression.

Figure 3

Cox regression for overall survival analysis according to the CDH1 haplotypes (A) and the restricted CDH1 haplotype model (B). (A) Overall survival curves of all patients with mGC (n = 59) based on their different CDH1 haplotype; (B) Overall survival curves of all patients with mGC (n = 59) according to coupled rs16260 and rs1801552 polymorphisms. * indicates a significant difference compared to the P7 haplotype (panel A) and coupled AT polymorphism (panel B).