Mutations of the human E-cadherin (CDH1) gene

Berx, Geert; Becker, Karl‐Friedrich; Höfler, Heinz; Roy, Frans van

doi:10.1002/(sici)1098-1004(1998)12:4<226::aid-humu2>3.0.co;2-d

Cited by 521 publications

(325 citation statements)

References 59 publications

(55 reference statements)

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“…E-cadherin is a transmembrane calcium-dependent protein and is mainly expressed at the basolateral membrane of epithelial cells, where it has important roles in cell-cell adhesion at the adherens junctions to maintain epithelial integrity [29,30]. Heterozygous germline CDH1 mutations have been described in 18-40% of HDGC families [31][32][33][34][35].…”

Section: Genetics Of Hdgcmentioning

confidence: 99%

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Post

Gullo

Oliveira

et al. 2016

Advances in Experimental Medicine and Biology

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Familial clustering is seen in 10% of gastric cancer cases and approximately 1-3% of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis.Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterised by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT>1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.6

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Section: Genetics Of Hdgcmentioning

confidence: 99%

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Post

Gullo

Oliveira

et al. 2016

Advances in Experimental Medicine and Biology

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“…Several lines of evidence also suggest the involvement of Ecadherin/catenin complex in gastric carcinogenesis. Germ line E-cadherin mutation is responsible for the development of hereditary diffuse-type gastric carcinoma (Guilford et al, 1998), and somatic mutations in the E-cadherin or b-catenin gene have been reported in sporadic gastric carcinoma (Berx et al, 1998). We recently reported that in vivo adaptation of cagApositive H. pylori enhances its carcinogenic potential in a rodent model (Franco et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

et al. 2007

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Infection with Helicobacter pylori cagA-positive strains is associated with gastric adenocarcinoma. Intestinal metaplasia is a precancerous lesion of the stomach characterized by transdifferentiation of the gastric mucosa to an intestinal phenotype. The H. pylori cagA gene product, CagA, is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Tyrosine-phosphorylated CagA specifically binds to and activates SHP-2 phosphatase, thereby inducing cell-morphological transformation. We report here that CagA physically interacts with E-cadherin independently of CagA tyrosine phosphorylation. The CagA/E-cadherin interaction impairs the complex formation between E-cadherin and b-catenin, causing cytoplasmic and nuclear accumulation of b-catenin. CagA-deregulated b-catenin then transactivates b-catenin-dependent genes such as cdx1, which encodes intestinal specific CDX1 transcription factor. In addition to b-catenin signal, CagA also transactivates p21 WAF1/Cip1 , again, in a phosphorylation-independent manner. Consequently, CagA induces aberrant expression of an intestinal-differentiation marker, goblet-cell mucin MUC2, in gastric epithelial cells that have been arrested in G1 by p21 WAF1/Cip1 . These results indicate that perturbation of the E-cadherin/b-catenin complex by H. pylori CagA plays an important role in the development of intestinal metaplasia, a premalignant transdifferentiation of gastric epithelial cells from which intestinal-type gastric adenocarcinoma arises.

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“…Down-regulation of adhesion-related molecules in tumors have indicated that these proteins may function as TSs (Birchmeier, 1995;Bullions et al, 1997;Hoover et al, 1998;Hsieh et al, 1995;Simcha et al, 1996;Taverna et al, 1998). The loss of E-cadherinmediated cell adhesion was shown to be an important rate-limiting step in the progression of several somatic and hereditary carcinomas (Berx et al, 1998;Birchmeier et al, 1996;Guilford et al, 1998;Hirohashi, 1998;Perl et al, 1998). Alterations in desmosomal structure and/or composition have been correlated with the invasiveness and metastatic potential of carcinomas (Garrod et al, 1996;Garrod, 1995).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the gene encoding pinin/DRS/memA and evidence for its potential tumor suppressor function

Shi

Ouyang²,

Sugrue

2000

Oncogene

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Several cell adhesion-related proteins have been shown to act as tumor-suppressors (TS) in the neoplastic progression of epithelial-derived tumors. Pinin/DRS/memA was ®rst identi®ed in our laboratory and it was shown to be a cell adhesion-related molecule. Our previous study demonstrated that restoration of pinin expression in transformed cells not only positively in¯uenced cellular adhesive properties but also reversed the transformed phenotype to more epithelial-like. Here, we show by FISH analysis that the gene locus for pinin is within 14q13. The alignment of the pinin gene with STS markers localized the gene to the previously identi®ed TS locus D14S75-D14S288. Northern analyses revealed diminished pinin mRNA in renal cell carcinomas (RCC) and certain cancer cell lines. Immunohistochemical examination of tumor samples demonstrated absent or greatly reduced pinin in transitional cell carcinoma (TCC) and RCC tumors. TCC-derived J82 cells as well as EcR-293 cells transfected with full-length pinin cDNA demonstrated inhibition of anchorage-independent growth of cells in soft agar. Furthermore, methylation analyses revealed that aberrant methylation of pinin CpG islands was correlated with decreased/absent pinin expression in a subset of tumor tissues. These data lend signi®cant support to the hypothesis that pinin/DRS/memA may act as a tumor suppressor in certain types of cancers.

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Mutations of the human E-cadherin (CDH1) gene

Cited by 521 publications

References 59 publications

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

Characterization of the gene encoding pinin/DRS/memA and evidence for its potential tumor suppressor function

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