&lt;p&gt;CDH1 (E-Cadherin) Mutation and Gastric Cancer: Genetics, Molecular Mechanisms and Guidelines for Management&lt;/p&gt;

Shenoy, Santosh

doi:10.2147/cmar.s208818

Cited by 107 publications

(88 citation statements)

References 68 publications

(119 reference statements)

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“…In addition, a study reported two CTNNA1 variants (nonsense and frameshift) in 2 unrelated HDGC families both showed loss of -catenin protein expression and preserved E-cadherin expression. It is known that -catenin is a critical component of an adaptor protein complex to bridge E-cadherin and filaments of cytoskeleton, and maintains cell stability as well as inhibiting cell motility (7). Therefore, the variant in CTNNA1 detected in this study may hold the potential to impair normal function of E-cadherin-catenin complex and contribute to diffuse type pathology.…”

Section: Other Potential Deleterious Variants Identified In Candidatementioning

confidence: 79%

“…The genomic length of CDH1 is approximately 100kb, and it is transcribed into 4.5-kb mRNA followed by being translated to a 120kDa E-cadherin, a highly conserved transmembrane glycoprotein whose function is to maintain calcium-dependent cell-cell adhesion through association of cytosolic protein complex mainly formed by catenins (6,7). Therefore, susceptibility for gastric cancer in CDH1 mutation carriers is suggested to be attributed to aberrant E-cadherin function or protein loss, since a normal functioning E-cadherin is highly required by various signalling pathways and cross talks to maintain the balance of cell proliferation, motility and polarity (7). In addition, the estimated cumulative risk for CDH1 mutation carriers to develop GC by age 80 years is 67% for men and 83% for women (8).…”

Section: Introductionmentioning

confidence: 99%

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Investigation on Gastric Cancer Susceptibility Genes in Chinese Early-onset Diffuse Gastric Cancer

Feng

Zhang

et al. 2020

Preprint

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Abstract BackgroundDiffuse gastric cancer (DGC) is known as gastric cancer with diffuse type morphology. Early onset DGC is an indicator of suspicious hereditary diffuse gastric cancer (HDGC). HDGC patient are often less sensitive to chemotherapy and suffer from highly invasive late stage malignancy with poor prognosis. Such hereditary cancer syndrome is closely related to deleterious CDH1 germline variant. In addition, potential pathogenic germline variants in other candidate genes were also observed in HDGC families. However, the profile of gastric cancer (GC) susceptibility gene in Chinese HDGC patients is yet to be elucidated.MethodsTo investigate gastric cancer susceptibility genes in Chinese gastric cancer patients, we collected peripheral blood samples from 29 patients fulfilled both HDGC clinical diagnosis and genetic testing criteria updated on 2015 by IGCLC. Genomic DNA was extracted from peripheral blood followed by Whole Exome Sequencing (WES) with average sequencing depth of at least 100X. Gastric cancer predisposing SNV and Indel candidates were filtered based on population allele frequencies in public nucleotide polymorphism databases and pathogenic variant filtering process was performed to identify potential gastric cancer predisposing variant candidates. Immunohistochemistry was conducted on biopsies from patient who carries potential pathogenic CDH1 germline variant.ResultsIn general, 336296 germline non-synonymous variants were detected from 29 GC patients. According to the pathogenic variant filtering process, 25 germline variant candidates in 22 genes were identified as gastric cancer predisposing variant candidates. In addition, a novel splice-site variant, c.2165-1G>A (NM_004360.4), in CDH1 was detected in a Chinese early-onset HDGC patient who developed ovarian metastasis. Furthermore, IHC analysis on the ovarian cancer tissue from this patient demonstrated weakly to moderate staining of E-cadherin compared with positive control. Moreover, another two variants, CTNNA1 c.1975_1976del (NM_001903.2), APC c.-19+1G>A (NM_001127511.2), were suspicious of gastric cancer predisposing variants.ConclusionsThis study suggested that CDH1 c.2165-1G>A may act as a gastric cancer predisposing variant. In addition, to further investigate molecular mechanisms of early-onset gastric cancer, one may consider 22 genes observed in this study. Furthermore, the inconclusive results in this study warrant future investigation on gastric cancer susceptibility gene discovery that cohort selection may require more stringent conditions.

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Section: Other Potential Deleterious Variants Identified In Candidatementioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Investigation on Gastric Cancer Susceptibility Genes in Chinese Early-onset Diffuse Gastric Cancer

Feng

Zhang

et al. 2020

Preprint

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“…The loss of function due to methylation or deletion of CDKN2A has been observed in many cancers [24]. Additionally, the importance of DAPK and CDH1 in cancer has been revealed [25,26]. Because these four genes play an important role in carcinogenesis, we could not exclude the possibility that methylation of these genes renders them silent, and hence, directly contributes to carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Effect of DNMT3A polymorphisms on CpG island hypermethylation in gastric mucosa

et al. 2020

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Background CpG methylation of tumor suppressor genes occurs in the early stage of carcinogenesis. Detecting risk factors for aberrant CpG methylation is clinically important for predicting cancer development. DNA methyltransferase (DNMT) 3a is considered to play critical roles in the DNA methylation process during pathogenesis. In this study, we evaluated the association between DNMT3A polymorphisms (rs6733868 and rs13428812) and CpG methylation status in non-cancerous gastric mucosa. Methods We determined the DNMT3A genotype and CpG methylation status of 4 genes (p14ARF, p16INK4a, DAPK, and CDH1) in 510 subjects without gastric cancer. Helicobacter pylori (HP) infection status was determined by the rapid urease test, urea breath test, speculum examination, or serum antibody test. We determined the DNMT3A genotype using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). CpG methylation status was determined by methylation-specific polymerase chain reaction (MSP). When the methylated band was stronger than 10 ng/μL according to the DNA marker, we judged CpG island hypermethylation (CIHM) to be present. Associations between genotypes and susceptibilities were assessed by logistic regression analysis. Results The minor allele frequencies of both polymorphisms (rs6733868 and rs13428812) were lower in the CpG methylated groups of each of the 4 genes (p14ARF, p16INK4a, DAPK, and CDH1). Using a dominant genetic model, rs6733868 was significantly associated with the hypermethylation of each gene, whereas rs13428812 was associated with the methylation of 3 genes (all except p14ARF). When low-CIHM was defined as 1 or 2 CpG islands methylated and high-CIHM was defined as 3 or more CpG islands methylated, carrying the minor allele of rs6733868 was associated with both decreased low- and high-CIHM, and that of rs13428812 also was associated with a decrease. Comparing low-CIHM with high-CIHM, carrying the minor alleles of rs6733868 or rs13428812 was related to decreased susceptibility to high-CIHM. In HP-infected subjects, carrying the minor alleles of rs6733868 or rs13428812 had a significantly greater association with decreased susceptibility to high-CIHM. Conclusions Our study indicates that polymorphisms of DNMT3A are associated with the accumulation of gene methylation in gastric mucosa. Carrying the minor alleles of rs6733868 or rs13428812 inhibits aberrant gene methylations, which are typically enhanced by HP infection.

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“…On the other hand if we study the diffuse gastric cancer (usually hereditary), whose incidence is on the rising trend in the recent years in the younger population, it takes a small proportion of the total gastric cancers in the world but usually has fatal outcomes in these patients because of its aggressive nature of infiltrating the mucosal wall of the stomach known as linitis plastica. The outcomes are fatal because of their late presentation of symptoms in their course and by then the spread engulfs major organ systems of the body [4].…”

Section: Introductionmentioning

confidence: 99%

Significance of E-cadherin Gene Mutations in Patients With Hereditary Diffuse Gastric Cancer Syndrome: A Systematic Review

Goud

Mehkari

Mohammed

et al. 2020

Cureus

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Gastric cancer is the third-most fatal cancer in the world. Though over the years, we saw patients mostly with intestinal type accounting for the highest mortality rate, the recent rise of the diffuse form with germline E-cadherin (CDH1) mutations has added a whole new level of interest to study in detail about the association between CDH1 and diffuse gastric cancer (DGC). This introduced a set guideline formulated by Internal Gastric Cancer Linkage Consortium (IGCLC) for patients with family history of diffuse gastric cancer and invasive lobular breast cancer (ILBC). The analysis of this link was also important to set proper management protocol for patients who were CDH1 mutation carriers which now involves genetic counselling, endoscopic surveillance and screening and prophylactic total gastrectomy (PTG). The study was conducted in accordance to the 'PRISMA guidelines for reporting systematic review and meta-analysis'. Peer-reviewed studies were included from the PubMed database and relevant articles were selected to be included in the study. Appropriate inclusion/exclusion criteria with free full text English articles were applied while selecting the articles. A total of 10 studies on review with different study populations showed that of the 42 patients who were diagnosed with diffuse gastric cancer, 88% of them showed a positive germline E-cadherin gene mutation and 100% of the CDH1 mutation carriers showed microscopic changes of signet ring cell adenocarcinoma of the stomach. The beneficial effects of PTG with better survival rates and low mortality rates has outweighed other treatment modalities. Laparoscopic approach has proved to be more useful and a safer approach for gastrectomy surgeries with better post-operative management. The need for prophylactic mastectomy is also increased in the recent times and thus this requires a new set of guidelines for ILBC patients with hereditary diffuse gastric cancer (HDGC) syndrome.

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

Cited by 107 publications

References 68 publications

Investigation on Gastric Cancer Susceptibility Genes in Chinese Early-onset Diffuse Gastric Cancer

Investigation on Gastric Cancer Susceptibility Genes in Chinese Early-onset Diffuse Gastric Cancer

Effect of DNMT3A polymorphisms on CpG island hypermethylation in gastric mucosa

Significance of E-cadherin Gene Mutations in Patients With Hereditary Diffuse Gastric Cancer Syndrome: A Systematic Review

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