Samuel Peña-Llopis 1 , 2 , 3 , Silvia Vega-Rubín-de-Celis 1 , 2 , 3 , Arnold Liao 4 , Nan Leng 4 , Andrea Pavía-Jiménez 1 , 2 , 3 , Shanshan Wang 1 , 2 , 3 , Toshinari Yamasaki 1 , 2 , 3 , Leah Zhrebker 1 , 2 , 3 , Sharanya Sivanand 1 , 2 , 3 , Patrick Spence 1 , 2 , 3 , Lisa Kinch 5 , Tina Hambuch 4 , Suneer Jain 4 , Yair Lotan 6 , Vitaly Margulis 6 , Arthur I. Sagalowsky 6 , Pia Banerji Summerour 3 , 7 , Wareef Kabbani 8 , S. W. Wendy Wong 9 , Nick Grishin 5 , Marc Laurent 4 , Xian-Jin Xie 3 , Christian D. Haudenschild 4 , Mark T. Ross 9 , David R. Bentley 9 , Payal Kapur 8 , James Brugarolas 1 , 2 , 3 , †
10 June 2012
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. BAP1, 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 H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations 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.