@article{3a9ace44880345d4bb76677bb2d7b095,
title = "The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma",
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",
author = "Nargund, {Amrita M.} and Pham, {Can G.} and Yiyu Dong and Wang, {Patricia I.} and Osmangeyoglu, {Hatice U.} and Yuchen Xie and Omer Aras and Song Han and Toshinao Oyama and Shugaku Takeda and Ray, {Chelsea E.} and Zhenghong Dong and Mathieu Berge and Hakimi, {A. Ari} and Sebastien Monette and Lekaye, {Carl L.} and Koutcher, {Jason A.} and Leslie, {Christina S.} and Creighton, {Chad J.} and Nils Weinhold and William Lee and Tickoo, {Satish K.} and Zhong Wang and Cheng, {Emily H.} and Hsieh, {James J.}",
note = "Funding Information: This work was supported by The Jill and Jeffrey Weiss Fund to the Cure of Kidney Cancer and J. Randall and Kathleen L. MacDonald Kidney Cancer Research Fund. We thank Dr. Mihaela Lupu, Mr. Dov Winkleman, and Ms. Smrutiben A. Mehta for their technical support, and Dr. Victor Reuter for the initial assessment of mouse renal tumors. The MRI and LCP cores were supported by NIH grant P30CA008748. Publisher Copyright: {\textcopyright} 2017 The Author(s)",
year = "2017",
month = mar,
day = "21",
doi = "10.1016/j.celrep.2017.02.074",
language = "English",
volume = "18",
pages = "2893--2906",
journal = "Cell Reports",
issn = "2211-1247",
number = "12",
}