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.

项目概要 遗传性弥漫性胃癌综合征 (HDGC) 是一种与以下风险增加相关的遗传性疾病： 弥漫性胃癌和小叶乳腺癌。 HDGC 通常是由生殖细胞种系突变引起的 CDH1 基因，最近的证据已确定编码 α-E-catenin 的 CTNNA1 基因为新的假定 HDGC 风险基因。我们之前表明，12% 和 67% 的个体携带 CTNNA1 功能丧失 (LOF) 变异 多基因小组测试发现有弥漫性胃癌或乳腺癌的个人病史 分别。然而，鉴于先前收集的数据的局限性，癌症的范围和严重程度 目前与 CTNNA1 LOF 变异相关的风险仍不确定。阐明准确的癌症风险 CTNNA1 LOF 变异携带者的估计对于对受影响的患者进行适当的癌症风险管理至关重要 队列及其家庭成员。我们的初步数据表明CTNNA1 LOF变异携带者 可以成功招募为研究参与者，从而能够收集详细的个人和家族史 创建可用于癌症外显率分析的三代谱系。此外，我们 研究表明，CTNNA1 LOF 变异携带者可能具有不同的变异特异性癌症风险，并可能降低 胃癌风险与 C 端 LOF 变异相关。最后，我们证明患者来源的胃 可以成功建立类器官，包括来自 CTNNA1 LOF 变异携带者的类器官。综合起来我们 假设可以通过组合确定 CTNNA1 LOF 变异特异性癌症风险 改进的癌症外显率估计和患者来源的胃类器官模型。我们将 通过首先定义 CTNNA1 LOF 变异携带者的癌症外显率来研究这一假设 前瞻性 CTNNA1 家庭扩展 (CAFÉ) 研究，能够收集详细的个人和家庭信息 病史，随后创建将用于癌症治疗的三代谱系 渗透率分析。其次，我们将使用患者来确定CTNNA1变异特异性胃肿瘤的发生。 衍生的胃类器官，是重现胃癌发展的宝贵工具。我们将 利用这些源自患者的胃类器官来测试不同 CTNNA1 LOF 的致癌潜力 变种。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 变异的风险，这最终将有助于为这些变异的癌症风险管理决策提供信息 受影响的患者及其家人。