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
Puertollano, Rosa; Ferguson, Shawn M; Brugarolas, James et al. (2018) The complex relationship between TFEB transcription factor phosphorylation and subcellular localization. EMBO J 37:
Wang, Tao; Lu, Rong; Kapur, Payal et al. (2018) An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors. Cancer Discov 8:1142-1155
Carbone, Michele; Amelio, Ivano; Affar, El Bachir et al. (2018) Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine. Cell Death Differ 25:1885-1904
Kaushik, Akash K; DeBerardinis, Ralph J (2018) Applications of metabolomics to study cancer metabolism. Biochim Biophys Acta Rev Cancer 1870:2-14
Ho, Thai Huu; Kapur, Payal; Eckel-Passow, Jeanette E et al. (2017) Multicenter Validation of Enhancer of Zeste Homolog 2 Expression as an Independent Prognostic Marker in Localized Clear Cell Renal Cell Carcinoma. J Clin Oncol 35:3706-3713
Gu, Yi-Feng; Cohn, Shannon; Christie, Alana et al. (2017) Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade. Cancer Discov 7:900-917
Eckel-Passow, Jeanette E; Serie, Daniel J; Cheville, John C et al. (2017) BAP1 and PBRM1 in metastatic clear cell renal cell carcinoma: tumor heterogeneity and concordance with paired primary tumor. BMC Urol 17:19
Ho, Thai H; Kapur, Payal; Joseph, Richard W et al. (2016) Loss of histone H3 lysine 36 trimethylation is associated with an increased risk of renal cell carcinoma-specific death. Mod Pathol 29:34-42
Chen, Wenfang; Hill, Haley; Christie, Alana et al. (2016) Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539:112-117
Joseph, Richard W; Kapur, Payal; Serie, Daniel J et al. (2016) Clear Cell Renal Cell Carcinoma Subtypes Identified by BAP1 and PBRM1 Expression. J Urol 195:180-7

Showing the most recent 10 out of 16 publications