CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions

Herrera-Pariente, Cristina; Carot, Laura; Moreira, Leticia

doi:http://dx.doi.org/10.1007/s10120-024-01504-7

CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions

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Herrera-Pariente C, Bonjoch L, Muñoz J, Fernàndez G, Soares de Lima Y, Mahmood R, et al. CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions. Gastric Cancer. 2024 Jul;27(4):747-59. DOI: 10.1007/s10120-024-01504-7

Abstract

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 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 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.