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

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.

An Investigation Towards Understanding the Role of CDH1 Gene in Different Types of Breast Cancers

At recent age breast cancer attracts the attention of both the medical and the scientific community for its deadly occurrence throughout the globe as it is considered to be happened due to genetic aberration. Out of several genes expressed, it is found that cadherin 1, type 1 (CDH1) is responsible in several ways to control the metabolic order in human. Very recently it has been shown that deregulation of the function of protein E-cadherin, expressed from CDH1 plays an important role in lobular breast cancer. In order to understand the root cause of this recent claim, we focus on CDH1 gene whether the genetic information translated due to any deviation/alteration/modification in its sequence is related for the occurrence of the several other types of this deadly disease. Towards this end, study of the available genomic sequences of CDH1 gene obtained from the Sanger Database for 79 patients, suffering from various types of breast cancer, clearly emphasizes that alternation/modification in the sequence of the CDH1 gene can be detrimental. This would affect the regular function of the cell which may have a potential role in damaging the different types of breast tissues, causing malfunction and leading to breast cancers.

Diagnosis of MALT Lymphoma from Surveillance Endoscopy of a Patient with a CDH1 Gene Germline Mutation

Carriers of the mutated CDH1 gene have an increased risk of developing early-onset signet-ring cell (diffuse) gastric cancer. We present a case of a young patient with a confirmed mutation of the CDH1 gene, who was diagnosed with a gastric marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) from surveillance endoscopy. He underwent Helicobacter pylori eradication treatment and was subsequently submitted to a total prophylactic gastrectomy. The surgical specimen only revealed foci of signet-ring cell carcinoma (SRCC) in situ without lymphoma signs. We highlight here the occurrence of other pathology in high-risk patients as well as its possible influence on the decision to perform gastrectomy.

An investigation towards understanding the role of CDH1 gene in different types of Breast Cancers

At recent age breast cancer attracts the attention of both the medical and the scientific community for its deadly occurrence throughout the globe as it is considered to be happened due to genetic aberration. Out of several genes expressed, it is found that cadherin 1, type 1 (CDH1) is responsible in several ways to control the metabolic order in human. Hence we focus on CDH1 gene whether any deviation in it especially alteration/modification in its sequence is responsible for the occurrence of this deadly disease. Towards this end study of the available genomic sequences of CDH1 gene of several patients, suffering from various types of breast cancer (obtained from the Sanger Database), are studied. The results emphasizes that alternation/modification in the sequence of the CDH1 gene affect its regular function which may have a potential role in damaging the different types of breast tissues, causing malfunction and leading to breast cancers in patients.

p-120 Catenin is a Useful Diagnostic Biomarker for Distinguishing Plasmacytoid and Sarcomatoid Variants From Conventional Urothelial Carcinoma

Context.— Plasmacytoid urothelial carcinoma (PC-UC) is an aggressive variant of urothelial carcinoma (UC), characterized by loss of E-cadherin (E-Cad)–mediated intercellular adhesion. Loss of E-Cad by immunohistochemistry can help diagnosis PC-UC; however, sensitivity is limited. Expression of other cadherin-catenin adhesion complex members, that is, p-120 catenin (p-120) and β-catenin (B-Cat), which are diagnostically useful for lobular breast carcinoma, remains unknown in UC. Objective.— To determine the utility of p-120 and B-Cat in conventional and variant UC. Design.— E-cadherin, B-Cat, and p-120 immunohistochemistry was performed in 25 conventional UCs and 33 variant UCs, including 22 PC-UCs, 6 sarcomatoid UCs (SUCs), and 5 micropapillary UCs. Membranous staining for all biomarkers was considered normal; however, any cytoplasmic staining or an absence of staining was considered diagnostically abnormal. Next-generation sequencing was performed on 8 PC-UC cases. Results.— E-cadherin, B-Cat, and p-120 showed membranous staining in all conventional and micropapillary UCs. In contrast, most PC-UCs were negative for E-Cad (17 of 22; 77%) with an additional 2 of 22 cases (9%) showing cytoplasmic with partial membranous staining. p-120 catenin demonstrated cytoplasmic or negative staining in 21 of 22 cases (95%). Most SUCs showed an absence of E-Cad (5 of 6; 83%) and cytoplasmic or negative p-120 in 5 of 6 cases (83%). Staining for B-Cat was also abnormal in a subset of PC-UCs and SUCs. Five PC-UC cases that harbored CDH1 gene variants were p-120 cytoplasmic positive. Conclusions.— p-120 catenin is a useful adjunct biomarker to E-Cad in the clinically important distinction of PC-UC and SUC from conventional UC. In particular, the combination of cytoplasmic p-120 and loss of E-Cad is strongly supportive of PC-UC and SUC.