Evaluation of the BAP1 tumor suppressor gene in renal cell carcinoma

BAP1抑癌基因在肾细胞癌中的评价

基本信息

批准号：
9008030
负责人：
James Brugarolas
金额：
$ 32.99万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-03 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9008030
关键词：
Accounting Affect Alleles Animal Model BAP1 gene Behavior Benign Binding Biochemical Biology Cancer cell line Cell Line Cell Maintenance Cell Proliferation Cells Cessation of life ChIP-seq Chromatin Chromosomes Chromosomes, Human, Pair 14 Chromosomes, Human, Pair 9 Classification Clear Cell Clinic Complement Complex Coupled DNA Binding Data Development Evaluation Event Exhibits Foundations Gel Chromatography Gene Expression Gene Expression Profile Generations Genes Genetic Engineering Genetically Engineered Mouse Genets Genomics Health Human Implant Incidence Individual Inhibition of Cell Proliferation Kidney Kidney Neoplasms Knockout Mice Laboratories Link Loss of Heterozygosity Malignant Epithelial Cell Malignant Neoplasms Mediating Modeling Molecular Molecular Biology Molecular Genetics Mus Mutant Strains Mice Mutate Mutation Outcome Pathway interactions Patients Publishing Renal Cell Carcinoma Renal carcinoma Reporting Research Role Scaffolding Protein Series Site Stem cells Testing Tumor Suppression Tumor Suppressor Genes United States VHL gene VHL mutation Workplace base cancer cell cell type exome sequencing forkhead protein gene discovery host cell factor C1 human cancer mouse model innovation insight kidney cell model development mouse model mutant novel oncology reconstitution research study tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Kidney cancer affects over 270,000 individuals and accounts for more than 110,000 deaths yearly worldwide. In the United States, 60,920 new cases and 13,120 deaths of kidney cancer were estimated in 2011, and the incidence is rising. We have discovered that the gene BAP1 is inactivated in 15% of kidney tumors. We found that tumors with BAP1 mutations tend not to have mutations in another gene, PBRM1. Mutations in BAP1 or PBRM1 were observed in 70% of all renal tumors, however, whereas BAP1 mutation was associated with aggressive features (high tumor grade), tumors with PBRM1 mutations exhibited more benign features. Since mutated genes are ultimately responsible for the behavior of cancer cells, these results have substantial implications. These findings establish the foundation for a classification of kidney cancer based on mutated genes. Furthermore, we reported recently that BAP1- and PBRM1-mutant tumors are associated with different biology and disparate outcomes. The median overall survival for patients with BAP1-mutant tumors is 1.9 years, whereas it is 5.4 years for patients with PBRM1-mutant tumors. Thus, our discoveries are already impacting the clinic. In this proposal, experiments are proposed to determine, through a series of biochemical and molecular biology experiments, how BAP1 protects kidney cells from tumor development, and to create a genetically-engineered model of kidney cancer in the mouse. This project is a logical extension of our discovery that BAP1 is mutated in kidney cancer and leverages an outstanding research platform in the laboratory. A deeper understanding of how BAP1 functions coupled with better animal models should pave the way for better treatments for patients.

描述（由申请人提供）：全世界每年有超过 270,000 人受肾癌影响，并导致超过 110,000 人死亡。在美国，2011年估计有60,920例肾癌新发病例和13,120例死亡，并且发病率正在上升。我们发现 BAP1 基因在 15% 的肾肿瘤中失活。我们发现具有 BAP1 突变的肿瘤往往不会在另一个基因 PBRM1 中发生突变。然而，在 70% 的肾肿瘤中观察到 BAP1 或 PBRM1 突变，虽然 BAP1 突变与侵袭性特征（高肿瘤级别）相关，但具有 PBRM1 突变的肿瘤表现出更多良性特征。由于突变基因最终对癌细胞的行为负责，因此这些结果具有重大意义。这些发现为基于突变基因的肾癌分类奠定了基础。此外，我们最近报道，BAP1 和 PBRM1 突变肿瘤与不同的生物学和不同的结果相关。 BAP1 突变肿瘤患者的中位总生存期为 1.9 年，而 PBRM1 突变肿瘤患者的中位总生存期为 5.4 年。因此，我们的发现已经对临床产生了影响。在该提案中，拟通过一系列生化和分子生物学实验来确定BAP1如何保护肾细胞免受肿瘤发展，并在小鼠中创建肾癌的基因工程模型。该项目是我们发现 BAP1 在肾癌中发生突变的逻辑延伸，并利用了实验室的杰出研究平台。更深入地了解 BAP1 的功能以及更好的动物模型应该为更好地治疗患者铺平道路。