Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients

Keller, Gisela; Vogelsang, H.; Becker, Ingrid; Plaschke, Susanne; Ott, Katja; Suriano, Gianpaolo; Mateus, Ana; Seruca, Raquel; Biedermann, Karin; Huntsman, David G.; Döring, Claudia; Holinski‐Feder, Elke; Neutzling, A; Siewert, J. R.; Höfler, Heinz

doi:10.1136/jmg.2003.015594

Cited by 104 publications

(93 citation statements)

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“…Moreover, GC risk is elevated in several other hereditary cancer syndromes, namely Lynch syndrome caused by germline mutations in one of the DNA mismatch repair genes [11][12][13], Li-Fraumeni syndrome caused by TP53 germline mutations [14][15][16], familial adenomatous polyposis caused by APC germline mutations [17,18], Peutz-Jeghers syndrome caused by STK11 germline mutations [19][20][21], juvenile polyposis syndrome caused by SMAD4 or BMPR1A germline mutations [22,23], and hereditary breast or ovarian cancer syndrome caused by BRCA1 or BRCA2 germline mutations [10,24,25].…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…14 Using functional in vitro assays, we demonstrated that cells expressing pathogenic CDH1 missense mutations fail to aggregate and become more invasive, in comparison with cells expressing wild-type (WT) E-cadherin, 5,12,[15][16][17][18][19][20][21][22] supporting their pathogenic relevance.…”

Section: Introductionmentioning

confidence: 83%

“…E-cadherin mutants T340A, A634V, R749W, E757K, E781D, P799R and V832M found in the HDGC context, 16,18,19,21,[34][35][36][37][38] were constructed by site-directed mutagenesis in the entry vector CDH1pENTR 221 (Clone ID: IOH46767, Invitrogen, Grand Island, NY, USA), following the protocol described by Wang and Wilkinson. 41 By LR recombination reaction, the open reading frame was subcloned in the pEF6/Myc-His vector (Invitrogen).…”

Section: Plasmids Constructionmentioning

confidence: 99%

“…5,12,[15][16][17][18][19]21 The slow aggregation assay showed that all the mutants have an impact on the cell-cell adhesion ability but the type of aggregation showed distinct phenotypes (Figure 7a). Comparing with the compact aggregates formed by the WT E-cadherin-expressing cells, some mutants display smaller cellular aggregates, such as mutants T340A, A634V, R749W, P799R and V832M, and others exhibited a close-to-isolated phenotype, as observed for mutants E757K and E781D, very similar to the phenotype of Mock cells.…”

Section: Cdh1 Missense Mutations Affect E-cadherin Subcellular Localimentioning

confidence: 99%

“…We selected a panel of seven HDGC missense mutations (five intracellular and two extracellular) that have been proven to be pathogenic, 16,18,19,21,[34][35][36][37][38] and studied the ability of the mutant proteins to interact with direct E-cadherin binding partners using proximity ligation assays (PLA), a new tool to detect in situ proteinprotein interactions. 39,40 Fundamentally, PLA is a method where protein-recognition events are converted into detectable DNA molecules.…”

Section: Introductionmentioning

confidence: 99%

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The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC

et al. 2012

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In hereditary diffuse gastric cancer (HDGC), CDH1 germline gene alterations are causative events in 30% of the cases. In 20% of HDGC families, CDH1 germline mutations are of the missense type and the mutation carriers constitute a problem in terms of genetic counseling and surveillance. To access the pathogenic relevance of missense mutations, we have previously developed an in vitro method to functionally characterize them. Pathogenic E-cadherin missense mutants fail to aggregate and become more invasive, in comparison with cells expressing the wild-type (WT) protein. Herein, our aim was to develop a complementary method to unravel the pathogenic significance of E-cadherin missense mutations. We used cells stably expressing WT E-cadherin and seven HDGC-associated mutations (five intracellular and two extracellular) and studied by proximity ligation assays (PLA) how these mutants bind to fundamental regulators of E-cadherin function and trafficking. We focused our attention on the interaction with: p120, b-catenin, PIPKIc and Hakai. We showed that cytoplasmic E-cadherin mutations affect the interaction of one or more binding partners, compromising the E-cadherin stability at the plasma membrane and likely affecting the adhesion complex competence. In the present work, we demonstrated that the study of the interplay between E-cadherin and its binding partners, using PLA, is an easy, rapid, quantitative and highly reproducible technique that can be applied in routine labs to verify the pathogenicity of E-cadherin missense mutants for HDGC diagnosis, especially those located in the intracellular domain of the protein. Keywords: HDGC; E-cadherin; CDH1 mutations; E-cadherin trafficking; E-cadherin binding partners; diagnostic method INTRODUCTIONHereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome characterized by a high risk of developing diffuse gastric cancer 1-3 and lobular breast cancer 4-6 during life-time. CDH1 germline gene alterations (mutations or deletions), resulting in E-cadherin inactivation, are the only causative events described till now and were identified in approximately 30% of HDGC cases. 2,3,7 To date, 122 different germline mutations have been described in these families, 8 being the majority of them of the nonsense type, leading to alternative premature termination codons. 3 This type of CDH1 mutant transcripts is commonly downregulated by nonsensemediated decay leading to E-cadherin loss of function 9 and these patients are considered high-risk carriers and are counseled to perform prophylactic total gastrectomy. 10 In about 20% of HDGC families, carriers show CDH1 germline missense mutations 11 and, in contrast to truncating mutations, their pathogenic significance is not straightforward, therefore constituting a problem in terms of genetic counseling and surveillance.In 2004, Fitzgerald and Caldas 10 suggested that the significance of CDH1 missense mutations should be assessed in at least four affected members within a HDGC family in combination with functional and

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Founder and Recurrent CDH1 Mutations in Families With Hereditary Diffuse Gastric Cancer

Kaurah

MacMillan

Boyd

et al. 2007

JAMA

410

349

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Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients

Cited by 104 publications

References 33 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

The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC

Founder and Recurrent CDH1 Mutations in Families With Hereditary Diffuse Gastric Cancer

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