BAP1 loss defines a new class of renal cell carcinoma

By Samuel Peña-Llopis, Silvia Vega-Rubin-de-Celis, A. Liao, N. Leng, Andrea Pavía-Jiménez, Shanshan Wang, Toshinari Yamasaki, Leah Zhrebker, S. Sivanand, Patrick Spence and 17 more. Nature Genetics, 2012

912 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/30249fbee1572b5782ae957c31405d521a25ebb2

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Citations in the corpus

• Learning the human chromatin network from all ENCODE ChIP-seq data (2015, background): “HCFC1 binds largely to active promoters [43] and is involved in biological processes, such as cell cycle progression [51, 55] and oncogenesis [50, 13, 53].”
• Signatures of mutational processes in human cancer (2013, neutral): “In these cancers the mutation characteristics were different (SupplementaryFig.98),bearingthehallmarksofsomatichypermutation associatedwithAID,whichisoperativeduringthegenerationof immunologicaldiversity 20 .”