Characterization of a Recurrent Germ Line Mutation of the <i>E-Cadherin</i> Gene: Implications for Genetic Testing and Clinical Management

Suriano, Gianpaolo; Yew, Sandie; Ferreira, Paulo Michel Pinheiro; Senz, Janine; Kaurah, Pardeep; Ford, James M.; Longacre, Teri A.; Norton, Jeffrey A.; Chun, Nicolette M.; Young, Sean; Oliveira, Maria José; MacGillivray, B; Rao, Arundhati; Sears, Dawn; Jackson, Charles E.; Boyd, Jeff; Yee, Cindy J.; Deters, Carolyn A.; Pai, G. Shashidhar; Hammond, Lyn S.; McGivern, Bobbi; Medgyesy, Diane; Sartz, Denise; Arun, Banu K.; Oelschlager, Brant K.; Upton, Mellisa P.; Neufeld-Kaiser, Whitney; Silva, Orlando E.; Donenberg, Talia; Kooby, David A.; Sharma, Shobha; Jonsson, Björn; Grönberg, Henrik; Gallinger, Steve; Seruca, Raquel; Lynch, Henry T.; Huntsman, David G.

doi:10.1158/1078-0432.ccr-05-0247

Cited by 151 publications

(128 citation statements)

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“…Genetic alterations, as LOH, which seem to be acquired later in HDGC progression, could be then targeted with drugs such as EGFR and ␣5-␤1-integrinblocking antibodies or transforming growth factor-␤-R small synthetic molecules to prevent cells from migrating and metastasis from establishing. [35][36][37][38][39][40] In conclusion, our data support the previously published rate of CDH1 promoter hypermethylation as a 2nd-hit in HDGC primary tumors, and adds LOH as a key mechanism, mainly in metastatic lesions. Because of the concomitance and heterogeneity of these alterations in neoplastic lesions and the plasticity of hypermethylated promoters during tumor initiation and progression, drugs targeting only epigenetic alterations might not be effective, particularly in patients with metastatic HDGC.…”

Section: Discussionsupporting

confidence: 91%

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

et al. 2009

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Background & Aims:Hereditary diffuse gastric cancer (HDGC) families carry CDH1 heterozygous germline mutations; their tumors acquire complete CDH1 inactivation through "2nd-hit" mechanisms. Most frequently, this occurs via promoter hypermethylation (epigenetic modification), and less frequently via CDH1 mutations and loss of heterozygosity (LOH). We quantified the different 2nd hits in CDH1 occurring in neoplastic lesions from HDGC patients. Methods: Samples were collected from 16 primary tumors and 12 metastases from 17 patients among 15 HDGC families; CDH1 mutations, LOH, and promoter hypermethylation were analyzed. E-cadherin protein expression and localization were determined by immunohistochemistry. Results: Somatic CDH1 epigenetic and genetic alterations were detected in lesions from 80% of HDGC families and in 75% of all lesions analyzed (21/28). Of the 28 neoplastic lesions analyzed, promoter hypermethylation was found in 32.1%, LOH in 25%, both alterations in 17.9%, and no alterations in 25%. Half of the CDH1 2nd hits in primary tumors were epigenetic modifications, whereas a significantly greater percentage of 2nd hits in metastases were LOH (58.3%; P ‫؍‬ .0274). Different neoplastic lesions from the same patient frequently displayed distinct 2nd-hit mechanisms. Different 2nd-hit mechanisms were also detected in the same tumor sample. Conclusion: The 2nd hit in CDH1 frequently occurs via epigenetic changes in HDGC primary tumors and LOH in metastases. Because of the concomitance and heterogeneity of these alterations in neoplastic lesions and the plasticity of hypermethylated promoters during tumor initiation and progression, drugs targeting only epigenetic alterations might not be effective, particularly in patients with metastatic HDGC.

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Section: Discussionsupporting

confidence: 91%

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

et al. 2009

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“…Heterozygous germline CDH1 mutations have been described in 18-40% of HDGC families [31][32][33][34][35]. The frequency of CDH1 mutations seems to be highly variable, which may be related to the variable incidence of GC across different geographic regions.…”

Section: Genetics Of Hdgcmentioning

confidence: 99%

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

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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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“…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%

“…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%

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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Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management

Cited by 151 publications

References 30 publications

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

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

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