BAP1 loss defines a new class of renal cell carcinoma

Samuel Peña-Llopis, Silvia Vega-Rubín-De-Celis, Arnold Liao, Nan Leng, Andrea Pavía-Jiménez, Shanshan Wang, Toshinari Yamasaki, Leah Zhrebker, Sharanya Sivanand, Patrick Spence, Lisa Kinch, Tina Hambuch, Suneer Jain, Yair Lotan, Vitaly Margulis, Arthur I Sagalowsky, Pia Banerji Summerour, Wareef Kabbani, S. W Wendy Wong, Nick V GrishinMarc Laurent, Xian-Jin Xie, Christian D. Haudenschild, Mark T. Ross, David R. Bentley, Payal Kapur, James B Brugarolas

Research output: Contribution to journalArticle

495 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)751-759
Number of pages9
JournalNature genetics
Volume44
Issue number7
DOIs
StatePublished - Jul 1 2012

ASJC Scopus subject areas

  • Genetics

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    Peña-Llopis, S., Vega-Rubín-De-Celis, S., Liao, A., Leng, N., Pavía-Jiménez, A., Wang, S., Yamasaki, T., Zhrebker, L., Sivanand, S., Spence, P., Kinch, L., Hambuch, T., Jain, S., Lotan, Y., Margulis, V., Sagalowsky, A. I., Summerour, P. B., Kabbani, W., Wong, S. W. W., ... Brugarolas, J. B. (2012). BAP1 loss defines a new class of renal cell carcinoma. Nature genetics, 44(7), 751-759. https://doi.org/10.1038/ng.2323