BAP1 loss defines a new class of renal cell carcinoma.
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.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Samuel
S
Peña-Llopis
Silvia
S
Vega-Rubín-de-Celis
Arnold
A
Liao
Nan
N
Leng
Andrea
A
Pavía-Jiménez
Shanshan
S
Wang
Toshinari
T
Yamasaki
Leah
L
Zhrebker
Sharanya
S
Sivanand
Patrick
P
Spence
Lisa
L
Kinch
Tina
T
Hambuch
Suneer
S
Jain
Yair
Y
Lotan
Vitaly
V
Margulis
Arthur I
AI
Sagalowsky
Pia Banerji
PB
Summerour
Wareef
W
Kabbani
S W Wendy
SW
Wong
Nick
N
Grishin
Marc
M
Laurent
Xian-Jin
XJ
Xie
Christian D
CD
Haudenschild
Mark T
MT
Ross
David R
DR
Bentley
Payal
P
Kapur
James
J
Brugarolas
D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D059472:Exome; D005260:Female; D015870:Gene Expression / Q000235:genetics; D051863:Host Cell Factor C1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
C400134:BAP1 protein, human; D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase