Defining the phenotype and cancer penetrance of CTNNA1 loss-of-function germline variants

项目总结 遗传性弥漫性胃癌综合征(HDGC)是一种遗传性疾病，与 弥漫性胃癌和小叶性乳腺癌。虽然HDGC典型地是由 Cdh1基因，新近发现的编码-E-catenin的ctnna1基因是一种新的hdgc基因。 风险基因。我们之前的研究表明，12%和67%的CTNNA1功能丧失(LOF)变异个体 在多基因小组检测中确认有弥漫性胃癌或乳腺癌的个人病史 分别进行了分析。然而，鉴于之前收集的数据的局限性，癌症的范围和程度 与CTNNA1中LOF变异相关的风险目前仍不确定。阐明准确的癌症风险 对CTNNA1 LOF变异携带者的估计是允许对这种受影响的癌症风险进行适当管理的关键 以及他们的家庭成员。我们的初步数据显示CTNNA1 LOF变异携带者 可以成功地招募为研究参与者，从而能够收集详细的个人和家庭历史 通过创建可用于癌症外显性分析的三代家系。此外，我们 显示CTNNA1 LOF变异携带者可能具有不同的变异特异性癌症风险，潜在地降低 与C末端LOF变异相关的胃癌风险。最后，我们证明了患者衍生的胃 可以成功地建立包括CTNNA1 LOF变异载体的有机类化合物。总而言之，我们 假设CTNNA1 LOF变异特异性癌症风险可以通过联合 改进的癌症外显率估计和患者衍生的胃器官模型。我们会 首先通过定义CTNNA1 LOF变异携带者的癌症外显率来研究这一假说 未来CTNNA1家庭扩展研究(CAFé)，能够收集详细的个人和家庭信息 病史，以及随后将用于癌症的三代家系的创建 外显性分析。其次，我们将使用患者-来确定CTNNA1变异特异性的胃肿瘤发生。 衍生的胃器官，这是重述胃癌发展的宝贵工具。我们会 利用这些患者来源的胃有机物质来测试不同CTNNA1 LOF的致癌潜力 变种。总之，这项提案的研究结果将对建立变异型特异性癌症至关重要 CTNNA1 LOF变种的风险，这最终将有助于为这些变种的癌症风险管理决策提供信息 受影响的患者及其家属。

PROJECT SUMMARY Hereditary diffuse gastric cancer syndrome (HDGC) is a hereditary condition associated with increased risk of diffuse gastric cancer and lobular breast cancer. While HDGC is classically caused by germline mutations in the CDH1 gene, recent evidence has identified the CTNNA1 gene, coding for -E-catenin, as a new putative HDGC risk gene. We previously showed that 12% and 67% of individuals with a CTNNA1 loss-of-function (LOF) variant identified on multigene panel testing had a personal history of diffuse gastric cancer or breast cancer respectively. However, given limitations of previously collected data the extent and magnitude of the cancer risks associated with LOF variants in CTNNA1 remain uncertain at this time. Elucidating accurate cancer risk estimates for CTNNA1 LOF variant carriers is critical to allow for proper cancer risk management of this affected cohort as well as their family members. Our preliminary data demonstrates that CTNNA1 LOF variant carriers can be successfully recruited as study participants, enabling collection of detailed personal and family history with creation of three-generation pedigrees that can be used for cancer penetrance analyses. Furthermore, we show that CTNNA1 LOF variant carriers may have differing variant-specific cancer risks, with potentially reduced gastric cancer risk associated with C-terminal LOF variants. Finally, we demonstrate that patient-derived gastric organoids, including from CTNNA1 LOF variant carriers, can be successfully established. Taken together we hypothesize that CTNNA1 LOF variant-specific cancer risks can be established through a combination of improved cancer penetrance estimates and patient-derived gastric organoid models. We will investigate this hypothesis by first defining the cancer penetrance of CTNNA1 LOF variant carriers through the prospective CTNNA1 Family Expansion (CAFÉ) Study, enabling collection of detailed personal and family medical history, with subsequent creation of three-generation pedigrees that will be utilized for cancer penetrance analysis. Secondly, we will determine CTNNA1 variant-specific gastric tumorigenesis using patient- derived gastric organoids, which are invaluable tools for recapitulating gastric cancer development. We will utilize these patient-derived gastric organoids to test the carcinogenic potential of different CTNNA1 LOF variants. Together, the study results from this proposal will be critical for establishing variant-specific cancer risks for CTNNA1 LOF variants, which will ultimately help inform cancer risk management decisions for these affected patients and their families.