Molecular Pathogenesis
E-cadherin is a transmembrane protein that is predominantly expressed at the basolateral membrane of epithelial cells, where it exerts cell-cell adhesion and invasion-suppression functions [Nagar et al 1996].
E-cadherin is one member of the cadherin family of molecules, all of which are transmembrane glycoproteins mediating calcium-dependent cell-cell adhesion [Takeichi 1991, Berx et al 1995]. E-cadherin is critical for establishing and maintaining polarized and differentiated epithelia during development [Keller 2002]. It also plays important roles in signal transduction, differentiation, gene expression, cell motility, and inflammation. The activity of E-cadherin in cell adhesion is dependent on its association with the actin cytoskeleton via undercoat proteins called catenins (α-, β-, and γ-) [Jou et al 1995, Kallakury et al 2001].
A role for E-cadherin in tumor development is well established [Wijnhoven et al 2000] because many human carcinomas (e.g., skin, lung, breast, urologic, gastric, colon, pancreatic, ovarian) exhibit reduced E-cadherin expression relative to their normal cellular counterparts [Giroldi et al 2000, Karayiannakis et al 2001, Tsanou et al 2008, Ch'ng & Tan 2009, Kuner et al 2009]. Loss of E-cadherin expression is seen in most diffuse gastric cancers and in lobular breast cancers; expression is usually maintained in intestinal gastric cancers and ductal breast cancers [Hirohashi 2000].
Cells deficient in E-cadherin lose their ability to adhere to each other and consequently become invasive and metastasize [Birchmeier 1995, Perl et al 1998]. The causal effect of E-cadherin loss or dysregulation in tumorigenesis has been demonstrated using carcinoma cell lines and transgenic models [Hsu et al 2000]. Examination of in situ diffuse gastric cancer lesions from a prophylactic total gastrectomy specimen have shown this loss of E-cadherin to be an early initialing event that leads to invasion [Humar et al 2007].
Loss of heterozygosity is a common phenomenon seen in association with loss of expression of tumor suppressor genes [Knudson 1971]. The tumor suppressor function of E-cadherin is supported through evidence of the loss of expression of the other CDH1 allele [Grady et al 2000, Barber et al 2008, Oliveira et al 2009].
Gene structure.
CDH1 comprises 16 exons that span 100 kb. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. To date, more than 155 germline pathogenic variants have been reported in families with hereditary diffuse gastric cancer [Gayther et al 1998, Guilford et al 1998, Richards et al 1999, Yoon et al 1999, Dussaulx-Garin et al 2001, Humar et al 2002, Jonsson et al 2002, Oliveira et al 2002, Brooks-Wilson et al 2004, Keller et al 2004, Suriano et al 2005, Frebourg et al 2006, Rodriguez-Sanjuan et al 2006, Kaurah et al 2007, Masciari et al 2007, More et al 2007, Roviello et al 2007, Van Domselaar et al 2007, Oliveira et al 2009, Ghaffari et al 2010, Mayrbaeurl et al 2010].
The pathogenic variants are primarily truncating, usually through frameshift variants, exon/intron splice site variants, and single-nucleotide variants [Gayther et al 1998, Guilford et al 1998, Richards et al 1999, Humar et al 2002, Oliveira et al 2002, Brooks-Wilson et al 2004].
Pathogenic missense variants have also been identified in some families [Shinmura et al 1999, Yoon et al 1999, Oliveira et al 2002, Brooks-Wilson et al 2004]. The pathogenicity of missense variants can be investigated through in vitro analysis, although only on a research basis [Suriano et al 2003].
Large deletions make up approximately 4% of these variants [Oliveira et al 2009, Yamada et al 2014].
The pathogenic variants are distributed throughout the gene. However, there are reports of the same pathogenic variant being found in several unrelated families [Hansford et al 2015].
A founder variant has been seen in four families from Newfoundland, Canada [Kaurah et al 2007]. The pathogenic variant NM_004360.3:c.2398delC (p.Arg800AlafsTer16) was confirmed by haplotype analysis in these families.
Germline pathogenic variants have been identified in several ethnic groups; germline variants appear to be rare in countries in which the rates of sporadic gastric cancer are high [Hansford et al 2015]. The reason is not known; it may be postulated that the differences in genetic backgrounds of the various ethnicities may have different effects on the viability of embryos with mutated heterozygous germline CDH1 pathogenic variants.
Normal gene product. The longest transcript, NM_004360.3, is 4.5 kb and is translated into a 135-kd precursor polypeptide of E-cadherin. This in turn is rapidly processed to the mature 120-kd form. The mature E-cadherin protein contains three domains: the extracellular domain encoded by exons 4-13, the transmembrane domain encoded by parts of exons 13 and 14, and the highly conserved cytoplasmic domain encoded by the rest of exon 14 to exon 16.
The large extracellular
domain (N-terminal) is made up of five tandem cadherin repeats each containing about 110 amino acid residues [
Oliveira et al 2003,
Bryant & Stow 2004]. The extracellular domain homodimerizes with E-cadherin expressed in neighboring epithelial cells in a Ca
2+-dependent manner, thus enabling cell-cell adhesion at the zonula adherens junctions of the homotypic neighboring cells.
The cytoplasmic
domain (C-terminal) interacts with the cytoskeleton actin filaments through α-, β-, and γ-catenins and p120
ctn catenins in regulating the intracellular signaling pathways. β-catenin attaches to the C-terminal region of E-cadherin and then to α-catenin, which then binds to the F-actin microfilaments of the cytoskeleton. p120
ctn binds to a juxtamembrane site of E-cadherin cytoplasmic tail [
Bryant & Stow 2004]. p120 also provides complex stability [
Weis & Nelson 2006].
E-cadherin expression is controlled through a complex transcriptional regulation system.
Intron 2 of
CDH1 has been implicated in the normal expression of the
gene. Intron 2, which accounts for the majority of the noncoding
intronic sequences of
CDH1, contains conserved
cis-regulatory elements.
Stemmler et al [2005] performed a study in which
deletion of murine
genomic intron 2 led to inactivation of the gene during early embryonic development.
Abnormal gene product. See Molecular Pathogenesis.
