BAP1 loss defines a new class of renal cell carcinoma.
BAP1 loss defines a new class of renal cell carcinoma.
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DOI：
10.1038/ng.2323
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发表时间：
2012-06-10
期刊：
影响因子：
30.8
通讯作者：
Brugarolas, James
中科院分区：
文献类型：
--
作者：
Pena-LlopiS, Samuel;Vega-Rubin-de-Celis, Silvia;Liao, Arnold;Leng, Nan;Pavia-Jimenez, Andrea;Wang, Shanshan;Yamasaki, Toshinari;Zhrebker, Leah;Sivanand, Sharanya;Spence, Patrick;Kinch, Lisa;Hambuch, Tina;Jain, Suneer;Lotan, Yair;Margulis, Vitaly;Sagalowsky, Arthur I.;Summerour, Pia Banerji;Kabbani, Wareef;Wong, S. W. Wendy;Grishin, Nick;Laurent, Marc;Xie, Xian-Jin;Haudenschild, Christian D.;Ross, Mark T.;Bentley, David R.;Kapur, Payal;Brugarolas, James
肾细胞癌（RCC）的分子发病机制知之甚少。全基因组和外显子组测序，然后进行创新的肿瘤移植物分析（以准确确定突变等位基因比例），确定了几个推定的两次打击肿瘤抑制基因，包括BAP 1。BAP 1是一种核去泛素化酶，在15%的透明细胞RCC中失活。BAP 1与肿瘤移植物中的HCF-1共分馏并结合。破坏HCF-1结合基序的突变会损害BAP 1介导的细胞增殖抑制，但不会损害H2 AK 119 ub 1去泛素化。BAP 1缺失使体外RCC细胞对遗传毒性应激敏感。有趣的是，BAP 1和PBRM 1突变在肿瘤中存在相关性（P=3×10−5），少数RCC中BAP 1和PBRM 1的联合缺失与横纹肌样特征相关（q=0.0007）。BAP 1和PBRM 1调节看似不同的基因表达程序，BAP 1丢失与高肿瘤分级相关（q=0.0005）。我们的研究结果为RCC的综合病理学和分子遗传学分类奠定了基础，为利用遗传脆弱性进行亚型特异性治疗铺平了道路。
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. BAP1, 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 H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations 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.
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DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
8
作者：
Jensen, DE;Proctor, M;Rauscher, FJ
通讯作者：
Rauscher, FJ
影响因子：
4
作者：
Abdel-Rahman MH;Pilarski R;Cebulla CM;Massengill JB;Christopher BN;Boru G;Hovland P;Davidorf FH
通讯作者：
Davidorf FH