BAP1 loss defines a new class of renal cell carcinoma

被引：738

作者：

Pena-LlopiS, Samuel ^{[2
,3
]}

Vega-Rubin-de-Celis, Silvia ^{[1
,2
,3
]}

Liao, Arnold ^{[4
]}

Leng, Nan ^{[4
]}

Pavia-Jimenez, Andrea ^{[1
,2
,3
]}

Wang, Shanshan ^{[1
,2
,3
]}

Yamasaki, Toshinari ^{[1
,2
,3
]}

Zhrebker, Leah ^{[2
,3
]}

Sivanand, Sharanya ^{[1
,2
,3
]}

Spence, Patrick ^{[1
,3
]}

Kinch, Lisa ^{[5
]}

Hambuch, Tina ^{[4
]}

Jain, Suneer ^{[4
]}

Lotan, Yair ^{[6
]}

Margulis, Vitaly ^{[6
]}

Sagalowsky, Arthur I. ^{[6
]}

Summerour, Pia Banerji ^{[3
,7
]}

Kabbani, Wareef ^{[8
]}

Wong, S. W. Wendy ^{[9
]}

Grishin, Nick ^{[5
]}

Laurent, Marc ^{[4
]}

Xie, Xian-Jin ^{[3
]}

Haudenschild, Christian D. ^{[4
]}

Ross, Mark T. ^{[9
]}

Bentley, David R. ^{[9
]}

Kapur, Payal ^{[8
]}

Brugarolas, James ^{[1
,2
,3
]}

机构：

[1] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[2] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA

[3] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[4] Illumina Inc, San Diego, CA USA

[5] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

[6] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA

[7] Univ Texas SW Med Ctr Dallas, Dept Clin Genet, Dallas, TX 75390 USA

[8] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[9] Illumina Cambridge Ltd, Saffron Walden, England

来源：

NATURE GENETICS | 2012年 / 44卷 / 07期

基金：

美国国家卫生研究院;

关键词：

BRCA1-ASSOCIATED PROTEIN-1; OCULOCUTANEOUS ALBINISM; UBIQUITIN HYDROLASE; SOMATIC MUTATIONS; FREQUENT MUTATION; TUMOR-SUPPRESSOR; GENE-EXPRESSION; FACTOR-I; P-GENE; COMPLEX;

D O I：

10.1038/ng.2323

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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.

引用

页码：751 / U174

页数：11

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