CTNND1 通过影响细胞间相互作用参与早发性胃癌的种系易感性。
CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions.
发表日期：2024 May 25
作者：
Cristina Herrera-Pariente, Laia Bonjoch, Jenifer Muñoz, Guerau Fernàndez, Yasmin Soares de Lima, Romesa Mahmood, Miriam Cuatrecasas, Teresa Ocaña, Sandra Lopez-Prades, Gemma Llargués-Sistac, Xavier Domínguez-Rovira, Joan Llach, Irina Luzko, Marcos Díaz-Gay, Conxi Lazaro, Joan Brunet, Carmen Castillo-Manzano, María Asunción García-González, Angel Lanas, Marta Carrillo, Raquel Hernández San Gil, Enrique Quintero, Nuria Sala, Gemma Llort, Lara Aguilera, Laura Carot, Pilar Diez-Redondo, Rodrigo Jover, Teresa Ramon Y Cajal, Joaquín Cubiella, Antoni Castells, Francesc Balaguer, Luis Bujanda, Sergi Castellví-Bel, Leticia Moreira
来源：
Disease Models & Mechanisms
摘要：
CDH1和CTNNA1仍然是遗传性胃癌的主要基因。然而，他们只能解释一小部分疑似遗传基础的胃癌病例。在这项研究中，我们的目的是为早发性胃癌患者（EOGC； < 50 岁）鉴定新的遗传基因。对 20 名 EOGC 患者进行种系外显子组测序，并通过基因组测序在独立队列中复制相关结果。在 152 名患者中，CTNND1 作为一个有趣的候选基因脱颖而出，因为它的蛋白质产物 (p120ctn) 直接与 E-钙粘蛋白相互作用。我们通过基因编辑生成两个敲除 CTNND1 细胞模型并使用慢病毒递送系统引入检测到的遗传变异来进行功能表征。我们通过球体建模评估了 β-连环蛋白和 E-钙粘蛋白水平、细胞脱离以及 E-钙粘蛋白定位和细胞间相互作用。三种 CTNND1 种系变异 [c.28_29delinsCT, p.(Ala10Leu)； c.1105C > T，p.(Pro369Ser)； c.1537A > G, p.(Asn513Asp)] 在我们的 EOGC 队列中被鉴定。编码 CTNND1 变体的细胞表现出改变的 E-钙粘蛋白水平和细胞间相互作用。此外，位于 E-cadherin/p120ctn 结合域关键区域的 p.(Pro369Ser) 变体显示 E-cadherin 错误定位。CTNND1 的缺陷可能通过改变 E-cadherin 和，因此，细胞与细胞之间的相互作用。在本研究中，CTNND1 种系变异解释了 2% (3/172) 的病例，尽管需要在更大的外部队列中进行进一步研究。© 2024。作者。
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).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.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.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.© 2024. The Author(s).