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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：
8632102
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/8632102
关键词：
Accounting Affect Alleles Animal Model BRCA1 Associated Protein-1 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 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 public health relevance reconstitution research study tumor tumorigenesis

项目摘要

Project Summary 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.

项目摘要肾癌影响超过270，000人，每年全球有超过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例肾癌死亡，发病率正在上升。我们已经发现，BAP 1基因在15%的肾脏肿瘤中失活。我们发现有BAP1突变的肿瘤往往没有另一个基因PBRM 1的突变。BAP1突变或然而，在70%的肾肿瘤中观察到PBRM 1，而BAP 1突变与肾肿瘤的发生相关。具有侵袭性特征（高肿瘤等级），具有PBRM 1突变的肿瘤表现出更多的良性特征。以来突变的基因最终负责癌细胞的行为，这些结果具有实质性意义。影响这些发现为基于突变的肾癌分类奠定了基础。基因.此外，我们最近报道，BAP 1和PBRM 1突变型肿瘤与不同的生物学和不同的结果。BAP1突变型肿瘤患者的中位总生存期为1.9 年，而PBRM 1突变型肿瘤患者为5.4年。因此，我们的发现已经影响诊所。在这个建议中，提出了实验来确定，通过一系列的生化和分子生物学实验，BAP 1如何保护肾细胞免受肿瘤发展的影响，并创造一个小鼠肾癌的基因工程模型。这个项目是一个合乎逻辑的延伸，发现BAP1在肾癌中突变，并利用了一个杰出的研究平台，实验室更深入地了解BAP 1的功能，再加上更好的动物模型，为患者提供更好的治疗方法。