Evaluation of the BAP1 tumor suppressor gene in renal cell carcinoma

描述(申请人提供)：肾癌影响超过27万人，全球每年有超过11万人死于肾癌。在美国，2011年估计有60920例新的肾癌病例和13120例死亡病例，而且发病率还在上升。我们发现，在15%的肾脏肿瘤中，BAP1基因是失活的。我们发现，带有BAP1突变的肿瘤往往不会有另一种基因PBRM1的突变。BAP1或PBRM1突变出现在70%的肾脏肿瘤中，而BAP1突变与肿瘤的侵袭性特征(高级别)有关，而PBRM1突变的肿瘤表现出更多的良性特征。由于突变的基因最终决定了癌细胞的行为，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突变的肿瘤与不同的生物学和不同的结果有关。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。在这项提案中，建议进行实验，通过一系列生化和分子生物学实验，确定BAP1如何保护肾细胞免受肿瘤发展的影响，并在小鼠身上建立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合乎逻辑的延伸，并利用了实验室中出色的研究平台。更深入地了解BAP1是如何发挥作用的，再加上更好的动物模型，应该为更好地治疗患者铺平道路。

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.