The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma.
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.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Amrita M
AM
Nargund
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Can G
CG
Pham
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Yiyu
Y
Dong
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Patricia I
PI
Wang
Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Hatice U
HU
Osmangeyoglu
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.
Yuchen
Y
Xie
Gerstner Sloan Kettering School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Omer
O
Aras
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Song
S
Han
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Toshinao
T
Oyama
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Shugaku
S
Takeda
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Chelsea E
CE
Ray
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Zhenghong
Z
Dong
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Mathieu
M
Berge
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
A Ari
AA
Hakimi
Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Sebastien
S
Monette
Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Carl L
CL
Lekaye
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Jason A
JA
Koutcher
Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Christina S
CS
Leslie
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Chad J
CJ
Creighton
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Nils
N
Weinhold
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
William
W
Lee
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Satish K
SK
Tickoo
Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, Ann Arbor, MI 48109, USA.
Zhong
Z
Wang
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.
Emily H
EH
Cheng
Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University, St. Louis, MO 63110, USA. Electronic address: jhsieh@wustl.edu.
James J
JJ
Hsieh
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000235:genetics; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D024002:HMGB Proteins / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D006869:Hydronephrosis / Q000235:genetics / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
D004268:DNA-Binding Proteins; D024002:HMGB Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; C496872:Pbrm1 protein, mouse; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; C045073:Cre recombinase; D019426:Integrases; C497446:VHL protein, human; C494469:VHL protein, mouse
HIF1; MTOR; PBRM1; STAT3; VHL; ccRCC; epigenetics; genetics; kidney cancer; mouse tumor model