scholarly journals Clinical spectrum and pleiotropic nature of CDH1 germline mutations

2019 ◽  
Vol 56 (4) ◽  
pp. 199-208 ◽  
Author(s):  
Joana Figueiredo ◽  
Soraia Melo ◽  
Patrícia Carneiro ◽  
Ana Margarida Moreira ◽  
Maria Sofia Fernandes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Genetic Alterations ◽  
Tumour Suppressor Gene ◽  
Diffuse Gastric Cancer ◽  
Loss Of Function ◽  
Lobular Breast Cancer ◽  
Cancer Syndrome ◽  
Risk Of Cancer ◽  
E Cadherin

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

scholarly journals Family’s History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form

2020 ◽  
Vol 21 (14) ◽  
pp. 4904
Author(s):  
Laura Caggiari ◽  
Mara Fornasarig ◽  
Mariangela De Zorzi ◽  
Renato Cannizzaro ◽  
Agostino Steffan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Susceptibility ◽  
Stop Codon ◽  
Case Reports ◽  
Premature Stop Codon ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
The Family ◽  
Hereditary Gastric Cancer ◽  
E Cadherin

Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10–18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families.

scholarly journals Loss of E-Cadherin Leads to Druggable Vulnerabilities in Sphingolipid Metabolism and Vesicle Trafficking

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 102
Author(s):  
Tom Brew ◽  
Nicola Bougen-Zhukov ◽  
Wilson Mitchell ◽  
Lyvianne Decourtye ◽  
Emily Schulpen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Synthetic Lethality ◽  
Vesicle Trafficking ◽  
Sphingolipid Metabolism ◽  
Mcf10a Cell ◽  
Diffuse Gastric Cancer ◽  
Loss Of Function ◽  
Cancer Syndrome ◽  
Increased Risk ◽  
Mcf10a Cells

Germline inactivating variants of CDH1 are causative of hereditary diffuse gastric cancer (HDGC), a cancer syndrome characterzsed by an increased risk of both diffuse gastric cancer and lobular breast cancer. Because loss of function mutations are difficult to target therapeutically, we have taken a synthetic lethal approach to identify targetable vulnerabilities in CDH1-null cells. We have previously observed that CDH1-null MCF10A cells exhibit a reduced rate of endocytosis relative to wildtype MCF10A cells. To determine whether this deficiency is associated with wider vulnerabilities in vesicle trafficking, we screened isogenic MCF10A cell lines with known inhibitors of autophagy, endocytosis, and sphingolipid metabolism. Relative to wildtype MCF10A cells, CDH1−/− MCF10A cells showed significantly greater sensitivity to several drugs targeting these processes, including the autophagy inhibitor chloroquine, the endocytosis inhibitors chlorpromazine and PP1, and the sphingosine kinase 1 inhibitor PF-543. Synthetic lethality was confirmed in both gastric and mammary organoid models of CDH1 loss, derived from CD44-Cre/Cdh1fl/fl/tdTomato mice. Collectively, these results suggest that both sphingolipid metabolism and vesicle trafficking represent previously unrecognised druggable vulnerabilities in CDH1-null cells and may lead to the development of new therapies for HDGC.

Screening E-Cadherin Germline Mutations in Italian Patients with Familial Diffuse Gastric Cancer: An Analysis in the District of Urbino, Region Marche, Central Italy

2003 ◽  
Vol 89 (3) ◽  
pp. 255-258 ◽  
Author(s):  
Francesco Graziano ◽  
Anna Maria Ruzzo ◽  
Italo Bearzi ◽  
Enrica Testa ◽  
Vittorio Lai ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Susceptibility ◽  
Central Italy ◽  
Germline Mutations ◽  
Pedigree Analysis ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Standard Polymerase Chain Reaction ◽  
E Cadherin

Aims & Background Hereditary diffuse gastric cancer is a recently defined cancer syndrome caused by inactivating, heterozygous germline mutations in the E-cadherin gene (CDH1). To date, 16 truncating germline CDH1 mutations have been described in hereditary diffuse gastric cancer families in different ethnic groups, but so far, no investigation has been addressed to Italian patients. In the District of Urbino, Region Marche, Central Italy, gastric cancer is the most common tumor in men and it is the second in women after breast cancer. In this area, we investigated CDH1 mutations in patients who fulfilled the hereditary diffuse gastric cancer criteria. Material and Methods Consecutive patients with diffuse gastric cancer were considered eligible for the study. After pedigree analysis, patients who met the International Gastric Cancer Linkage Consortium criteria were studied for CDH1 mutations. After blood samples collection and DNA extraction, standard polymerase chain reaction and sequencing techniques were used for CDH1 analysis. Results In a study population of 98 patients with diffuse gastric cancer, 11 patients (11%) showed familial clustering and 3 of them met the International Gastric Cancer Linkage Consortium criteria for hereditary diffuse gastric cancer. None of the 3 patients showed inactivating germline mutation in CDH1. Conclusions According to recent studies, the frequency of CDH1 inactivating germline mutations in patients who fulfil the hereditary diffuse gastric cancer criteria may be lower than that reported in early investigations. The results of the present study in a population of Italian patients seem to confirm these data. It is likely that unidentified mutations in CDH1 or other involved genes contribute to diffuse gastric cancer susceptibility.

E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer

1999 ◽  
Vol 14 (3) ◽  
pp. 249-255 ◽  
Author(s):  
Parry J. Guilford ◽  
Justin B.W. Hopkins ◽  
William M. Grady ◽  
Sanford D. Markowitz ◽  
Joseph Willis ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Germline Mutations ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Inherited Cancer ◽  
Inherited Cancer Syndrome ◽  
E Cadherin

scholarly journals E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 175
Author(s):  
Lyvianne Decourtye-Espiard ◽  
Nicola Bougen-Zhukov ◽  
Tanis Godwin ◽  
Tom Brew ◽  
Emily Schulpen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Hdac Inhibitors ◽  
Early Event ◽  
Diffuse Gastric Cancer ◽  
Lobular Breast Cancer ◽  
Wild Type ◽  
Cdh1 Gene ◽  
Gene Encoding ◽  
Increased Sensitivity ◽  
E Cadherin

Inactivating germline mutations in the CDH1 gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic CDH1 mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking CDH1 expression. CDH1−/− breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. CDH1-null cells were also sensitive to more class-specific HDAC inhibitors, but compared to the pan-inhibitors, these effects were less robust to genetic background. Increased sensitivity to entinostat was also observed in gastric organoids with both Cdh1 and Tp53 deletions. However, the deletion of Tp53 largely abrogated the sensitivity of the Cdh1-null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced Cdh1 expression in heterozygous Cdh1+/− murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic CDH1-deficient cancers.

scholarly journals Hereditary diffuse gastric cancer: association with lobular breast cancer

2007 ◽  
Vol 7 (1) ◽  
pp. 73-82 ◽  
Author(s):  
Kasmintan A. Schrader ◽  
Serena Masciari ◽  
Niki Boyd ◽  
Sara Wiyrick ◽  
Pardeep Kaurah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Lobular Breast Cancer

A RAND/UCLA appropriateness study of the management of familial gastric cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 16-16
Author(s):  
Matthew Dixon ◽  
Rajini Seevaratnam ◽  
Debrah Wirtzfeld ◽  
Robin S. McLeod ◽  
Lucy K. Helyer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Expert Panel ◽  
Diffuse Gastric Cancer ◽  
Lobular Breast Cancer ◽  
Mutation Status ◽  
Prophylactic Gastrectomy ◽  
Cdh1 Mutation ◽  
Risk Patients ◽  
History Of

16 Background: Hereditary diffuse gastric cancer (HDGC) makes up 0.1-0.3% of all gastric cancers. Management of patients with HDGC is inconsistent and there is disagreement regarding management. Methods: A multi-disciplinary expert panel of 16 physicians from 6 countries scored 47 scenarios using the RAND/UCLA Appropriateness Methodology. Appropriateness was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores (AS) from 1-3 were considered inappropriate, 4−6 uncertain, and 7−9, appropriate. Agreement was reached when 11 of 16 panelists scored the statement similarly. If a statement was agreed to be appropriate, it was given a necessity score (NS) in the same manner. AS and NS are reported if agreement was met. Results: Gastric cancer (GC) patients with a family history of diffuse gastric cancer (DGC), lobular breast cancer or multiple family members with GC should be referred for genetics assessment and multidisciplinary decision-making (AS 8.0). It is appropriate for patients with DGC to have CDH1 mutation testing in a family with: (1) two or more cases of GC, with at least one case of DGC diagnosed before the age of 50 (AS 8.0); (2) three or more cases of GC diagnosed at any age, one or more of which is DGC (AS 8.0); (3) a patient diagnosed with DGC and lobular breast cancer (AS 8.0); or (4) a patient diagnosed with DGC under the age of 35 (AS 7.0, NS 5.0). A prophylactic total gastrectomy should be offered to CDH1 mutation carriers 20 years or older (AS 7.0). Conclusions: The Gastric Cancer Processes of Care panelists have outlined high risk patients in whom CDH1 mutation status should be determined, and cases in which a prophylactic gastrectomy is appropriate.

scholarly journals Allosteric AKT Inhibitors Target Synthetic Lethal Vulnerabilities in E-Cadherin-Deficient Cells

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1359 ◽  
Author(s):  
Nicola Bougen-Zhukov ◽  
Yasmin Nouri ◽  
Tanis Godwin ◽  
Megan Taylor ◽  
Christopher Hakkaart ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Bioinformatic Analysis ◽  
Normal Breast ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Gastric Cancer Cells ◽  
Gene Encoding ◽  
Enhanced Sensitivity ◽  
Mcf10a Cells ◽  
E Cadherin

The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for hereditary diffuse gastric cancer syndrome (HDGC). Using cell viability assays, we identified that breast (MCF10A) and gastric (NCI-N87) cells lacking CDH1 expression are more sensitive to allosteric AKT inhibitors than their CDH1-expressing isogenic counterparts. Apoptosis priming and total apoptosis assays in the isogenic MCF10A cells confirmed the enhanced sensitivity of E-cadherin-null cells to the AKT inhibitors. In addition, two of these inhibitors, ARQ-092 and MK2206, preferentially targeted mouse-derived gastric Cdh1−/− organoids for growth arrest. AKT protein expression and activation (as measured by phosphorylation of serine 473) were differentially regulated in E-cadherin-null MCF10A and NCI-N87 cells, with downregulation in the normal breast cells, but upregulation in the gastric cancer cells. Bioinformatic analysis of the TCGA STAD dataset revealed that AKT3, but not AKT1 or AKT2, is upregulated in the majority of E-cadherin-deficient gastric cancers. In conclusion, allosteric AKT inhibitors represent a promising class of drugs for chemoprevention and chemotherapy of cancers with E-cadherin loss.

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