000135932 001__ 135932
000135932 005__ 20240627150549.0
000135932 0247_ $$2doi$$a10.1007/s10120-024-01504-7
000135932 0248_ $$2sideral$$a138932
000135932 037__ $$aART-2024-138932
000135932 041__ $$aeng
000135932 100__ $$aHerrera-Pariente, Cristina
000135932 245__ $$aCTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions
000135932 260__ $$c2024
000135932 5060_ $$aAccess copy available to the general public$$fUnrestricted
000135932 5203_ $$aBackground: CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC;<50 years old).
Methods: After germline exome sequencing in 20 EOGC patients and replication of relevant fndings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed β-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling.
Results: Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C>T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identifed in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization.
Conclusions: Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed.
000135932 536__ $$9info:eu-repo/grantAgreement/EC/HORIZON EUROPE/101079217/EU/TWINNING FOR A EUROPEAN CONSORTIUM OF RECTAL CANCER RESEARCH INSTITUTIONS THROUGH STEPPING UP SCIENTIFIC, TECHNOLOGICAL AND INNOVATION EXCELLENCE OF IORS/STEPUPIORS$$9info:eu-repo/grantAgreement/ES/ISCIII/PI16-00599$$9info:eu-repo/grantAgreement/ES/ISCIII/PI20-00113$$9info:eu-repo/grantAgreement/ES/ISCIII/PI21-00333$$9info:eu-repo/grantAgreement/ES/ISCIII/PI22-00537
000135932 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000135932 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000135932 700__ $$aBonjoch, Laia
000135932 700__ $$aMuñoz, Jenifer
000135932 700__ $$aFernàndez, Guerau
000135932 700__ $$aSoares de Lima, Yasmin
000135932 700__ $$aMahmood, Romesa
000135932 700__ $$aCuatrecasas, Miriam
000135932 700__ $$aOcaña, Teresa
000135932 700__ $$aLopez-Prades, Sandra
000135932 700__ $$aLlargués-Sistac, Gemma
000135932 700__ $$aDomínguez-Rovira, Xavier
000135932 700__ $$aLlach, Joan
000135932 700__ $$aLuzko, Irina
000135932 700__ $$aDíaz-Gay, Marcos
000135932 700__ $$aLazaro, Conxi
000135932 700__ $$aBrunet, Joan
000135932 700__ $$aCastillo-Manzano, Carmen
000135932 700__ $$aGarcía-González, María Asunción
000135932 700__ $$0(orcid)0000-0001-5932-2889$$aLanas, Ángel$$uUniversidad de Zaragoza
000135932 700__ $$aCarrillo, Marta
000135932 700__ $$aHernández San Gil, Raquel
000135932 700__ $$aQuintero, Enrique
000135932 700__ $$aSala, Nuria
000135932 700__ $$aLlort, Gemma
000135932 700__ $$aAguilera, Lara
000135932 700__ $$aCarot, Laura
000135932 700__ $$aDiez-Redondo, Pilar
000135932 700__ $$aJover, Rodrigo
000135932 700__ $$aRamon y Cajal, Teresa
000135932 700__ $$aCubiella, Joaquín
000135932 700__ $$aCastells, Antoni
000135932 700__ $$aBalaguer, Francesc
000135932 700__ $$aBujanda, Luis
000135932 700__ $$aCastellví-Bel, Sergi
000135932 700__ $$aMoreira, Leticia
000135932 7102_ $$11007$$2610$$aUniversidad de Zaragoza$$bDpto. Medicina, Psiqu. y Derm.$$cArea Medicina
000135932 773__ $$g27, 4 (2024), 747-759$$pGastric Cancer$$tGastric Cancer$$x1436-3291
000135932 8564_ $$s7522653$$uhttps://zaguan.unizar.es/record/135932/files/texto_completo.pdf$$yVersión publicada
000135932 8564_ $$s2481874$$uhttps://zaguan.unizar.es/record/135932/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000135932 909CO $$ooai:zaguan.unizar.es:135932$$particulos$$pdriver
000135932 951__ $$a2024-06-27-13:20:53
000135932 980__ $$aARTICLE