RESUMO
BACKGROUND: 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 findings 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 ß-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 identified 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.
Assuntos
Caderinas , Cateninas , delta Catenina , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Humanos , Masculino , Cateninas/genética , Cateninas/metabolismo , Feminino , Pessoa de Meia-Idade , Adulto , Caderinas/genética , Comunicação Celular , Idade de Início , Antígenos CDRESUMO
El cáncer colorrectal (CCR) representa una de las neoplasias más comunes en los países desarrollados y la segunda causa de muerte por cáncer en España. Se desarrolla mediante la acumulación de alteraciones genéticas y epigenéticas en la mucosa colónica, dando lugar a adenomas colorrectales y carcinomas invasivos. Este proceso multietapa hace que el CCR sea susceptible a la implementación de medidas preventivas como los programas de cribado. Para ello, hoy en día existen diferentes estrategias, aunque ninguna cumple las condiciones ideales de una prueba de cribado. En este contexto, se ha visto que diversas alteraciones moleculares implicadas en la carcinogénesis del CCR podrían contribuir a la generación de nuevos métodos no invasivos, sensibles y específicos. En la siguiente revisión se comentarán brevemente algunos de los biomarcadores no invasivos más relevantes para el diagnóstico del CCR
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