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BAP1 loss defines a new class of renal cell carcinoma
Journal article   Peer reviewed

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, …
Nature genetics, Vol.44(7), pp.751-759
06/10/2012
DOI: 10.1038/ng.2323
PMCID: PMC3788680
PMID: 22683710

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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)), [corrected] 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.
 Mutation Kidney Neoplasms - genetics Gene Expression - genetics Humans Middle Aged Carcinoma, Renal Cell - genetics Cell Growth Processes - physiology Male Kidney Neoplasms - metabolism Host Cell Factor C1 - metabolism Exome Tumor Suppressor Proteins - deficiency Tumor Suppressor Proteins - genetics Ubiquitin Thiolesterase - deficiency Ubiquitin Thiolesterase - metabolism Female Protein Interaction Domains and Motifs Nuclear Proteins - genetics Tumor Suppressor Proteins - metabolism Carcinoma, Renal Cell - pathology Cells, Cultured Nuclear Proteins - metabolism Transcription Factors - genetics Ubiquitin Thiolesterase - genetics Host Cell Factor C1 - genetics Transcription Factors - metabolism Carcinoma, Renal Cell - metabolism Kidney Neoplasms - pathology Aged

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