TY - JOUR
T1 - BAP1 loss defines a new class of renal cell carcinoma
AU - Peña-Llopis, Samuel
AU - Vega-Rubín-De-Celis, Silvia
AU - Liao, Arnold
AU - Leng, Nan
AU - Pavía-Jiménez, Andrea
AU - Wang, Shanshan
AU - Yamasaki, Toshinari
AU - Zhrebker, Leah
AU - Sivanand, Sharanya
AU - Spence, Patrick
AU - Kinch, Lisa
AU - Hambuch, Tina
AU - Jain, Suneer
AU - Lotan, Yair
AU - Margulis, Vitaly
AU - Sagalowsky, Arthur I
AU - Summerour, Pia Banerji
AU - Kabbani, Wareef
AU - Wong, S. W Wendy
AU - Grishin, Nick V
AU - Laurent, Marc
AU - Xie, Xian-Jin
AU - Haudenschild, Christian D.
AU - Ross, Mark T.
AU - Bentley, David R.
AU - Kapur, Payal
AU - Brugarolas, James B
N1 - Funding Information:
We recognize the individuals who participated in the study and who donated samples. We thank O. Sepulveda, A. Husain and A. Yadlapalli for technical support, S. Cohenour and D. Sheppard for assistance with contracts and regulatory considerations, Y. Machida (Mayo Clinic) for providing plasmids, B. Grossman (MD Anderson Cancer Center) for providing the UMRC cells, C. Camacho and N. Tomimatsu for irradiating cells, and the staff of the UT Southwestern Tissue Resource. This work was supported by a fellowship of excellence from Generalitat Valenciana (BPOSTDOC06/004 to S.P.-L.) and by the following awards to J.B.: a grant from the Cancer Prevention and Research Institute of Texas (RP101075), a Clinical Scientist Development Award from the Doris Duke Charitable Foundation, an American Cancer Society Research Scholar grant (115739) and a grant from the US. National Institutes of Health (RO1 CA129387). The tissue management shared resource is supported in part by the US National Cancer Institute (NCI) (1P30CA142543). J.B. is a Virginia Murchison Linthicum Scholar in Medical Research at UT Southwestern. The content herein is solely the responsibility of the authors and does not represent the official views of any of the granting agencies.
PY - 2012/7
Y1 - 2012/7
N2 - The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10-5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
AB - The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10-5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
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U2 - 10.1038/ng.2323
DO - 10.1038/ng.2323
M3 - Article
C2 - 22683710
AN - SCOPUS:84862988411
SN - 1061-4036
VL - 44
SP - 751
EP - 759
JO - Nature genetics
JF - Nature genetics
IS - 7
ER -