Germline cdh1 g212e missense variant: Combining clinical, in vitro and in vivo strategies to unravel disease Burden
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/10216/153766 |
Resumo: | E-cadherin, encoded by CDH1, is an essential molecule for epithelial homeostasis, whose loss or aberrant expression results in disturbed cell–cell adhesion, increased cell invasion and metas-tasis. Carriers of CDH1 germline mutations have a high risk of developing diffuse gastric cancer and lobular breast cancer, associated with the cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). The ubiquitous availability of cancer panels has led to the identification of an increasing amount of “incidental” CDH1 genetic variants that pose a serious clinical challenge. This has sparked intensive research aiming at an accurate classification of the variants and consequent validation of their clinical relevance. The present study addressed the significance of a novel CDH1 variant, G212E, identified in an unusually large pedigree displaying strong aggregation of diffuse gastric cancer. We undertook a comprehensive pipeline encompassing family data, in silico predictions, in vitro assays and in vivo strategies, which validated the deleterious phenotype induced by this genetic alteration. In particular, we demonstrated that the G212E variant affects the stability and localization, as well as the adhesive and anti-invasive functions of E-cadherin, triggering epithelial disruption and disorganization. Our findings illustrate the clinical implication of a complementary approach for effective variant categorization and patient management. |
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Germline cdh1 g212e missense variant: Combining clinical, in vitro and in vivo strategies to unravel disease BurdenCDH1 missense variantE-cadherinFunctional assaysHDGCE-cadherin, encoded by CDH1, is an essential molecule for epithelial homeostasis, whose loss or aberrant expression results in disturbed cell–cell adhesion, increased cell invasion and metas-tasis. Carriers of CDH1 germline mutations have a high risk of developing diffuse gastric cancer and lobular breast cancer, associated with the cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). The ubiquitous availability of cancer panels has led to the identification of an increasing amount of “incidental” CDH1 genetic variants that pose a serious clinical challenge. This has sparked intensive research aiming at an accurate classification of the variants and consequent validation of their clinical relevance. The present study addressed the significance of a novel CDH1 variant, G212E, identified in an unusually large pedigree displaying strong aggregation of diffuse gastric cancer. We undertook a comprehensive pipeline encompassing family data, in silico predictions, in vitro assays and in vivo strategies, which validated the deleterious phenotype induced by this genetic alteration. In particular, we demonstrated that the G212E variant affects the stability and localization, as well as the adhesive and anti-invasive functions of E-cadherin, triggering epithelial disruption and disorganization. Our findings illustrate the clinical implication of a complementary approach for effective variant categorization and patient management.MDPI20212021-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10216/153766eng2072-669410.3390/cancers13174359Figueiredo, JMercadillo, FMelo, SBarroso, AGonçalves, MDíaz-Tasende, JCarneiro, PRobles, LColina, FIbarrola, CPerea, JMorais-de-Sá, ESeruca, RUrioste, Minfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-29T14:41:18Zoai:repositorio-aberto.up.pt:10216/153766Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T00:06:49.366810Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Germline cdh1 g212e missense variant: Combining clinical, in vitro and in vivo strategies to unravel disease Burden |
title |
Germline cdh1 g212e missense variant: Combining clinical, in vitro and in vivo strategies to unravel disease Burden |
spellingShingle |
Germline cdh1 g212e missense variant: Combining clinical, in vitro and in vivo strategies to unravel disease Burden Figueiredo, J CDH1 missense variant E-cadherin Functional assays HDGC |
title_short |
Germline cdh1 g212e missense variant: Combining clinical, in vitro and in vivo strategies to unravel disease Burden |
title_full |
Germline cdh1 g212e missense variant: Combining clinical, in vitro and in vivo strategies to unravel disease Burden |
title_fullStr |
Germline cdh1 g212e missense variant: Combining clinical, in vitro and in vivo strategies to unravel disease Burden |
title_full_unstemmed |
Germline cdh1 g212e missense variant: Combining clinical, in vitro and in vivo strategies to unravel disease Burden |
title_sort |
Germline cdh1 g212e missense variant: Combining clinical, in vitro and in vivo strategies to unravel disease Burden |
author |
Figueiredo, J |
author_facet |
Figueiredo, J Mercadillo, F Melo, S Barroso, A Gonçalves, M Díaz-Tasende, J Carneiro, P Robles, L Colina, F Ibarrola, C Perea, J Morais-de-Sá, E Seruca, R Urioste, M |
author_role |
author |
author2 |
Mercadillo, F Melo, S Barroso, A Gonçalves, M Díaz-Tasende, J Carneiro, P Robles, L Colina, F Ibarrola, C Perea, J Morais-de-Sá, E Seruca, R Urioste, M |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Figueiredo, J Mercadillo, F Melo, S Barroso, A Gonçalves, M Díaz-Tasende, J Carneiro, P Robles, L Colina, F Ibarrola, C Perea, J Morais-de-Sá, E Seruca, R Urioste, M |
dc.subject.por.fl_str_mv |
CDH1 missense variant E-cadherin Functional assays HDGC |
topic |
CDH1 missense variant E-cadherin Functional assays HDGC |
description |
E-cadherin, encoded by CDH1, is an essential molecule for epithelial homeostasis, whose loss or aberrant expression results in disturbed cell–cell adhesion, increased cell invasion and metas-tasis. Carriers of CDH1 germline mutations have a high risk of developing diffuse gastric cancer and lobular breast cancer, associated with the cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). The ubiquitous availability of cancer panels has led to the identification of an increasing amount of “incidental” CDH1 genetic variants that pose a serious clinical challenge. This has sparked intensive research aiming at an accurate classification of the variants and consequent validation of their clinical relevance. The present study addressed the significance of a novel CDH1 variant, G212E, identified in an unusually large pedigree displaying strong aggregation of diffuse gastric cancer. We undertook a comprehensive pipeline encompassing family data, in silico predictions, in vitro assays and in vivo strategies, which validated the deleterious phenotype induced by this genetic alteration. In particular, we demonstrated that the G212E variant affects the stability and localization, as well as the adhesive and anti-invasive functions of E-cadherin, triggering epithelial disruption and disorganization. Our findings illustrate the clinical implication of a complementary approach for effective variant categorization and patient management. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021 2021-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/10216/153766 |
url |
https://hdl.handle.net/10216/153766 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2072-6694 10.3390/cancers13174359 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799135993139298304 |