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

doi:10.1016/j.celrep.2017.02.074

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 WeinholdWilliam Lee, Satish K. Tickoo, Zhong Wang, Emily H. Cheng, James J. Hsieh

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152 Scopus citations

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.

Original language	English
Pages (from-to)	2893-2906
Number of pages	14
Journal	Cell Reports
Volume	18
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2017.02.074
State	Published - Mar 21 2017

Keywords

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

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10.1016/j.celrep.2017.02.074

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Nargund, A. M., Pham, C. G., Dong, Y., Wang, P. I., Osmangeyoglu, H. U., Xie, Y., Aras, O., Han, S., Oyama, T., Takeda, S., Ray, C. E., Dong, Z., Berge, M., Hakimi, A. A., Monette, S., Lekaye, C. L., Koutcher, J. A., Leslie, C. S., Creighton, C. J., ... Hsieh, J. J. (2017). The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma. Cell Reports, 18(12), 2893-2906. https://doi.org/10.1016/j.celrep.2017.02.074

@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 = "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 = "2639-1856",

number = "12",

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Nargund, AM, Pham, CG, Dong, Y, Wang, PI, Osmangeyoglu, HU, Xie, Y, Aras, O, Han, S, Oyama, T, Takeda, S, Ray, CE, Dong, Z, Berge, M, Hakimi, AA, Monette, S, Lekaye, CL, Koutcher, JA, Leslie, CS, Creighton, CJ, Weinhold, N, Lee, W, Tickoo, SK, Wang, Z, Cheng, EH & Hsieh, JJ 2017, 'The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma', Cell Reports, vol. 18, no. 12, pp. 2893-2906. https://doi.org/10.1016/j.celrep.2017.02.074

TY - JOUR

T1 - The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma

AU - Nargund, Amrita M.

AU - Pham, Can G.

AU - Dong, Yiyu

AU - Wang, Patricia I.

AU - Osmangeyoglu, Hatice U.

AU - Xie, Yuchen

AU - Aras, Omer

AU - Han, Song

AU - Oyama, Toshinao

AU - Takeda, Shugaku

AU - Ray, Chelsea E.

AU - Dong, Zhenghong

AU - Berge, Mathieu

AU - Hakimi, A. Ari

AU - Monette, Sebastien

AU - Lekaye, Carl L.

AU - Koutcher, Jason A.

AU - Leslie, Christina S.

AU - Creighton, Chad J.

AU - Weinhold, Nils

AU - Lee, William

AU - Tickoo, Satish K.

AU - Wang, Zhong

AU - Cheng, Emily H.

AU - Hsieh, James J.

PY - 2017/3/21

Y1 - 2017/3/21

N2 - 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.

AB - 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.

KW - HIF1

KW - MTOR

KW - PBRM1

KW - STAT3

KW - VHL

KW - ccRCC

KW - epigenetics

KW - genetics

KW - kidney cancer

KW - mouse tumor model

UR - http://www.scopus.com/inward/record.url?scp=85015779370&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2017.02.074

DO - 10.1016/j.celrep.2017.02.074

M3 - Article

C2 - 28329682

AN - SCOPUS:85015779370

SN - 2639-1856

VL - 18

SP - 2893

EP - 2906

JO - Cell Reports

JF - Cell Reports

IS - 12

ER -

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

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