Cell Reports (Mar 2017)
The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma
- Amrita M. Nargund,
- Can G. Pham,
- Yiyu Dong,
- Patricia I. Wang,
- Hatice U. Osmangeyoglu,
- Yuchen Xie,
- Omer Aras,
- Song Han,
- Toshinao Oyama,
- Shugaku Takeda,
- Chelsea E. Ray,
- Zhenghong Dong,
- Mathieu Berge,
- A. Ari Hakimi,
- Sebastien Monette,
- Carl L. Lekaye,
- Jason A. Koutcher,
- Christina S. Leslie,
- Chad J. Creighton,
- Nils Weinhold,
- William Lee,
- Satish K. Tickoo,
- Zhong Wang,
- Emily H. Cheng,
- James J. Hsieh
Affiliations
- Amrita M. Nargund
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Can G. Pham
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Yiyu Dong
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Patricia I. Wang
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Hatice U. Osmangeyoglu
- Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Yuchen Xie
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Omer Aras
- Gerstner Sloan Kettering School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Song Han
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Toshinao Oyama
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Shugaku Takeda
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Chelsea E. Ray
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Zhenghong Dong
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Mathieu Berge
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- A. Ari Hakimi
- Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Sebastien Monette
- Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Carl L. Lekaye
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Jason A. Koutcher
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Christina S. Leslie
- Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Chad J. Creighton
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Nils Weinhold
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- William Lee
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Satish K. Tickoo
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Zhong Wang
- Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, Ann Arbor, MI 48109, USA
- Emily H. Cheng
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- James J. Hsieh
- Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA
- DOI
- https://doi.org/10.1016/j.celrep.2017.02.074
- Journal volume & issue
-
Vol. 18,
no. 12
pp. 2893 – 2906
Abstract
PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.
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