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

定义 CTNNA1 功能丧失种系变异的表型和癌症外显率

• 批准号: 10578417
• 负责人: Bryson William Katona
• 金额: $ 19.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578417
• 关键词: 3-Dimensional; Accounting; Adhesions; Affect; Architecture; Binding; Biological Assay; Biopsy; Breast Cancer Detection; C-terminal; CDH1 gene; Cadherins; Calcium; Carcinogenicity Tests; Cell membrane; Cell physiology; Cells; Clinical Management; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collection; Cytoplasmic Tail; Data; Development; Diffuse; Diffuse gastric cancer; Dysplasia; E-Cadherin; Enrollment; Event; Family; Family history of; Family member; Gastric Tissue; Generations; Genes; Genotype; Germ-Line Mutation; Goals; Heritability; Histology; Homeostasis; Individual; Inherited; Laboratories; Lobular; Malignant Neoplasms; Mediating; Medical; Medical History; Modeling; Molecular; Morphology; N-terminal; Organoids; Participant; Pathogenicity; Patients; Penetrance; Penetrance analysis; Phenotype; Proliferation Marker; Proteins; Recording of previous events; Regulation; Reporting; Risk; Risk Estimate; Risk Management; Serial Passage; Syndrome; TP53 gene; Time; Tissues; Tumor Markers; Uncertainty; Variant; Work; cancer risk; cohort; data collection methodology; gastric organoids; gastric tumorigenesis; genetic panel test; genetic pedigree; genomic profiles; improved; indexing; loss of function; malignant breast neoplasm; malignant stomach neoplasm; prospective; protein function; recruit; risk variant; screening; tool; tumor progression; tumorigenic; variant detection

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.

项目摘要 遗传性弥漫性胃癌综合征（HDGC）是一种遗传病，与增加的风险有关 弥漫性胃癌和小叶乳腺癌。虽然HDGC是由经典由种系突变引起的 CDH1基因，最近的证据已经确定了CTNNA1基因，编码为-E-catenin，是一种新的推定HDGC 风险基因。我们先前表明，有CTNNA1功能丧失（LOF）变体的个体中有12％和67％ 在多基因面板测试上确定有弥漫性胃癌或乳腺癌的个人病史 分别。但是，鉴于先前收集的数据的局限性癌症的程度和幅度 目前，与CTNNA1中LOF变体相关的风险仍然不确定。阐明准确的癌症风险 CTNNA1 LOF变体载体的估计对于允许适当的癌症风险管理至关重要 队列以及他们的家人。我们的初步数据表明CTNNA1 LOF变体载体 可以成功招募作为研究参与者，从而收集详细的个人和家族史 通过创建可用于癌症渗透分析的三代血统。此外，我们 证明CTNNA1 LOF变体载体可能具有不同的变异特异性癌症风险，并有可能降低 与C末端LOF变体相关的胃癌风险。最后，我们证明了患者衍生的胃 可以成功建立的器官，包括来自CTNNA1 LOF变体载体。总的来说我们 假设CTNNA1 LOF变体特异性癌症风险可以通过组合建立 改善了癌症的渗透率估计值和患者衍生的胃癌模型。我们将 通过首先定义CTNNA1 LOF变体载体的癌症渗透率来研究这一假设 潜在的CTNNA1家庭扩展（咖啡馆）研究，使详细的个人和家庭收集 病史，随后创建了三代血统，将用于癌症 渗透分析。其次，我们将使用患者 - 衍生的胃癌，这是概括胃癌发展的宝贵工具。我们将 利用这些患者衍生的胃癌来测试不同CTNNA1 LOF的致癌潜力 变体。总之，该提案的研究结果对于建立变异特异性癌症至关重要 CTNNA1 LOF变体的风险，最终将有助于为癌症风险管理决定这些决定 影响了患者及其家人。