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.

Public Health Relevance

Cancer is driven by mutations. We have discovered that the BAP1 gene is mutated in kidney cancer and defines a particular type of aggressive renal cancer. Herein experiments are proposed to obtain insight into how BAP1 normally suppresses kidney cancer development, and model kidney cancer in the mouse through the generation of genetically-engineered mice lacking BAP1 in the kidney.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA175754-01A1
Application #
8632102
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Johnson, Ronald L
Project Start
2013-12-03
Project End
2018-11-30
Budget Start
2013-12-03
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$329,925
Indirect Cost
$122,425
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Brugarolas, James (2014) Molecular genetics of clear-cell renal cell carcinoma. J Clin Oncol 32:1968-76
Pavía-Jiménez, Andrea; Tcheuyap, Vanina Toffessi; Brugarolas, James (2014) Establishing a human renal cell carcinoma tumorgraft platform for preclinical drug testing. Nat Protoc 9:1848-59