Characterization of the P373L E-cadherin germline missense mutation and implication for clinical management

Corso, Giovanni; Roviello, Franco; Paredes, Joana; Pedrazzani, Corrado; Novais, Marta; Correia, Joana; Marrelli, Daniele; Cirnes, Luı́s; Seruca, Raquel; Oliveira, Carla; Suriano, Gianpaolo

doi:10.1016/j.ejso.2007.03.001

Cited by 38 publications

(32 citation statements)

References 25 publications

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“…The initial observation of CDH1 promoter hypermethylation as the most common 2nd-hit mechanism 10,11,14 is consistent with the fact that only primary HDGC tumors have been analyzed. Our own results demonstrate the same when only primary tumors are considered (11/16; 68.8%).…”

Section: Discussionsupporting

confidence: 66%

“…15,16 Data from 27 tumors arising in 27 patients from the 13 HDGC families studied so far still indicate CDH1 promoter hypermethylation as the most common 2nd-hit mechanism of inactivation. 10,11,14 In contrast with studies on the 2nd-hit inactivation mechanism of genes causing other neoplastic syndromes, [17][18][19][20] somatic genetic alterations (mutations and loss of heterozygosity [LOH]) of CDH1 were uncommonly found. 10 -12,14 As a consequence, CDH1 promoter hypermethylation has been suggested as the basis for development of early detection tools as well as for chemoprophylaxis in unaffected CDH1 mutation carriers.…”

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confidence: 98%

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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: 66%

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confidence: 98%

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

et al. 2009

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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: 84%

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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“…This is particularly striking taking into account that a well-known ‘familial’ cancer such as breast cancer shows a familial aggregation of only about 12% [20]. In contrast with the high familial aggregation observed, only one deleterious E-cadherin germline mutation was identified even in families fulfilling the HDGC clinical criteria [13, 14]. In keeping with previous reports characterizing regions with a high prevalence of gastric cancer, the observed familial clustering may result from environmental factors and gene-environment interactions rather than autosomal dominant mutations.…”

Section: Discussionmentioning

confidence: 99%

“…CDH1 germline mutations were first described in three Maori families with autosomal dominant diffuse gastric cancer [11]; since then, additional germline mutations have been identified in families of different ethnic background (European, Japanese, Korean and African-American) [12]. Recently, we have detected the first germline mutation in the CDH1 gene in a family that fulfilled the HDGC criteria [13, 14]. …”

Section: Introductionmentioning

confidence: 98%

High Incidence of Familial Gastric Cancer in Tuscany, a Region in Italy

et al. 2007

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Objectives: Only 1% of diffuse gastric cancers occur in families with autosomal dominant gastric cancer susceptibility. Germline mutations in the E-cadherin gene account for the hereditary diffuse gastric cancer (HDGC) syndrome. We studied a large cohort of gastric cancer patients from Tuscany, a region in Italy, to evaluate the presence of familial clustering of gastric cancer. Methods: 238 pedigrees were retrospectively studied by structured interviews. All probands with diagnosed gastric cancer were contacted in-person or by phone and tumor types were assessed in first- and second-degree relatives. Familial aggregation was investigated in order to search for families with suspected HDGC. Results: Familial aggregation for gastric cancer was observed in 79 of 238 cases (33.2%). Among these, there were 64 families (81%) with one gastric cancer other than the proband, 10 families with two gastric cancers (12.7%) and 5 families with three gastric cancers (6.3%). Fourteen families fulfilled the HDGC clinical criteria, one of them presenting with a pathogenic germline mutation in the E-cadherin gene (7.1%). Conclusions: The prevalence of familial HDGC appears extremely high. Since only one pathogenic germline mutation was noted in a family fulfilling the HDGC clinical criteria, factors other than E-cadherin gene mutations may contribute to the familial clustering of HDGC.

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Characterization of the P373L E-cadherin germline missense mutation and implication for clinical management

Cited by 38 publications

References 25 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

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

High Incidence of Familial Gastric Cancer in Tuscany, a Region in Italy

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