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Cell Rep. 2017 Mar 21;18(12):2893-2906. doi: 10.1016/j.celrep.2017.02.074.

The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Gerstner Sloan Kettering School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
10
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
11
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
12
Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, Ann Arbor, MI 48109, USA.
13
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: chenge1@mskcc.org.
14
Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA. Electronic address: jhsieh@wustl.edu.

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.

KEYWORDS:

HIF1; MTOR; PBRM1; STAT3; VHL; ccRCC; epigenetics; genetics; kidney cancer; mouse tumor model

PMID:
28329682
PMCID:
PMC5431084
DOI:
10.1016/j.celrep.2017.02.074
[Indexed for MEDLINE]
Free PMC Article

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