CDH1 (E-Cadherin) Mutation and Gastric Cancer: Genetics, Molecular Mechanisms and Guidelines for Management

Abstract

Introduction: Germline mutation in CDH1 (E-cadherin) tumor suppressor gene is associated with hereditary diffuse gastric cancer (HDGC) and lobular breast cancers (LBC). E-Cadherin protein is necessary for physiological signaling pathways, such as cell proliferation, maintenance of cell adhesion, cell polarity and epithelial-mesenchymal transition. Dysregulation leads to tumor proliferation, invasion, migration and metastases. We review current perspectives in CDH1 genetics with molecular mechanisms and also discuss management strategies for this aggressive form of gastric cancer.

Methods: Relevant articles from PubMed/Medline and Embase (1994-2019) were searched and collected using the phrases "Hereditary diffuse gastric cancer, Familial gastric cancer, CDH1 mutation, E-Cadherin, Lobular breast cancer, Prophylactic total gastrectomy".

Results: Current guidelines suggest maintaining a high degree of suspicion of hereditary etiology and recommend testing for CDH1 mutations in patients with familial clustering of HDGC and LBC, especially onset at an early age (before 40 years). In families lacking CDH1 mutations but with high suspicion for hereditary predisposition, testing of CTNNA1 and other closely related HDGC susceptibility genes could be considered. Prophylactic total gastrectomy is recommended for individuals with identified pathogenic germline variants. Endoscopic surveillance with biopsies is recommended for those choosing to delay prophylactic gastrectomy.

Conclusion: Mutation or transcriptional silencing of the CDH1 gene is associated with familial diffuse gastric cancer. Further studies on the expression and the alteration in the proteins in the E-cadherin pathways may serve as biomarkers for early detection; stratify risk and selection of appropriate therapy in these families. Until then prophylactic total gastrectomy is recommended for individuals with CDH1 mutations and family history of diffuse gastric cancer. Endoscopic surveillance and biopsies by experienced gastroenterologists is recommended for those choosing not to have prophylactic gastrectomy and in individuals with CDH1 variants.

Keywords: CDH1 gene; E-cadherin functions; diffuse gastric cancer; lobular breast carcinoma.

Figure 1

Structure and function of E-Cadherin–catenin complex (Adherens Junction). E-cadherin glycoprotein consists of three structural domains, a single transmembrane domain bridging the cytosolic domain to the extracellular calcium-dependent domain consisting of five tandem repeats (all domains are represented in green color and block dots represent calcium ions). The extracellular motif binds to homophilic cadherin molecule from adjacent cells and this adhesion requires calcium ions which acts at a hinge and prevents the domain from flexing and provides it rigidity. The cytoplasmic tail of the E-cadherin protein interacts with filaments of cytoskeleton: actin through a set of adaptor proteins called catenin’s (p120, β-catenin, and α-catenin). This structure provides the cell stability and architecture and also inhibits individual cell motility.

Figure 2

Signaling pathways and cross talk, regulated by E-cadherin. E-cad/β-catenin/Wnt pathway :βcatenin plays a central role as an adaptor protein linking E-cadherin to the actin cytoskeleton in cell‐cell adhesion. It also remains a key component in the Wnt signaling. Under physiological conditions, cytoplasmic β-catenin remains in an inactive state by being bound to the APC/GSK3β/Axin/CK1 degradation complex and undergoes phosphorylation for ubiquitination. Wnt signaling inhibits this degradative process by phosphorylating and inhibiting the GSK3β complex. This raises the critical threshold of β-catenin in the cytoplasm required to translocate into the nucleus. Under permissive conditions which amplify aberrant Wnt signaling such as paracrine factors from tumor environment, cytokines from stromal cells and TNF-α from macrophages, β-catenin translocates into the nucleus and binds to TCF-4/LEF-1 proteins to induce Wnt target genes such as c-Myc, cyclins, MMP. This leads to uncontrolled cell proliferation and growth.– In the absence of E-cadherin, un-sequestered β-catenin released from the membrane-bound cadherin-catenin complex leads to excess cytoplasmic β-catenin. It has been demonstrated that β-catenin uses the same binding interface to engage TCF and E-cadherin ligands and cadherins have a superior binding affinity. There is a suggestion that as E-cad protein is lost there is excess un-sequestered cytoplasmic β-catenin that escapes degradation and enters the nucleus to bind to TCF and activate Wnt pathway. In addition to activating downstream Wnt associated genes, it is also demonstrated nuclear translocation of β-catenin represses PTEN expression. PTEN is a tumor suppressor and a critical regulator of AKT/MTOR pathway. Thus, the carefully balanced Wnt/β-catenin/E-cad functioning is tipped in favor of uncontrolled cell proliferation promoting oncogenesis – (Figure 2). E-cad/EGFR/RAS/RAF/MEK: Another function of E-cadherin is through its co-localization with EGFR at cell-cell contact and inhibiting EGFR pathways. Mutation of E-cadherin is associated with ligand-dependent activation of EGFR and downstream effectors through RAS/RAF/MEK pathways and also other pro-tumorigenic pathways such as FAK/c-Src and PI3K/AKT/MTOR pathway thus contributing to enhanced cell proliferation and motility. In addition, E-cad loss is associated with increased nuclear translocation of β-catenin into the nucleus as described earlier. This translocation of β-catenin represses PTEN expression. PTEN is a tumor suppressor and a critical regulator of AKT/MTOR pathway, , – (Figure 2). E-cad/P-120/Rho/MAPK pathway: The Rho family of GTPases belongs to the RAS superfamily. They act as binary molecular switches and regulate many aspects of intracellular cytoskeleton dynamics, motility and cell polarity, cell proliferation. Normally, when E-cad protein is lost the cells undergo apoptosis through a process called anoikis, a form of programmed cell death occurring after cellular detachment and loss of cell architecture and polarity. Functional analysis of activated RhoA mutations suggests that activated RhoA inhibits anoikis. Other mechanism of RhoA activation occurs indirectly through adhesion-dependent interaction with the p120 protein. Besides having a physiological role in adherens junction as described above, p120 protein (Figure 1) binds E-cadherin and stabilizes adherens junctions and suppresses both RhoA and NF-ĸB pathways. However, upon E-cadherin silencing, this negative regulation of RhoA is lost and p120 promotes cell growth by activating and modulating RhoGTPase and thus activating RAS/RAC/MAPK activity and also through Rho mediated activation of inflammatory NF-ĸB pathways (BCL, IL-6, TNF). Although H. pylori is associated with intestinal type of gastric carcinoma; it may be a confounding factor in diffuse gastric cancer. It is demonstrated that Cag A (cytotoxic-associated gene A), secreted by H. pylori may cause epigenetic silencing of the E-cad gene, thus activate Rho through GRB/SHP-2 and downstream RAF/MEK/ERK pathway, , –, – (Figure 2). E-cad/snail, slug, twist and Zeb-1pathway :E-cadherin also play an important developmental role in EMT transition by suppression of transcription factors: snail, slug, twist and Zeb-1. These factors are implicated in the differentiation of epithelial cell into mesenchymal cells (EMT). Loss of E-cadherin protein promotes epithelial to mesenchymal cell (EMT) transition and thus loss of cell polarity and activation of motility. Snail, Twist and Zeb-1, previously known to cause E-cadherin repression, were among the transcription factors up-regulated following E-cadherin loss. This loss of cellular architecture leads to a migratory, mesenchymal phenotype important in metastatic disease. Cells lose cytokeratin and E-cad markers and gain other mesenchymal markers such as vimentin and N-cadherin. Loss of E-cad protein could be due to germline mutation as observed in HDGC or due to overexpression of transcription repressor (snail/slug/twist/zeb) factors by advanced carcinomas which downregulates E-cad expression. This phenomenon is also called transcriptional silencing. This leads to invasion and metastases,,, (Figure 2).