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

基本信息

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
项目类别：
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

项目摘要

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通常是由生殖系突变引起的。 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 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。 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。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 末端 LOF 变异相关最后，我们证明了患者来源的胃癌。我们可以成功地建立类器官，包括来自 CTNNA1 LOF 变异载体的类器官。培养了可以通过组合确定CTNNA1 LOF变异特异性癌症风险我们将改进癌症外显率估计和患者来源的胃类器官模型。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，我们将使用患者确定 CTNNA1 变异特异性胃肿瘤发生衍生的胃类器官，这是重现胃癌发展的宝贵工具。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。