Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nat Genet. 2012 Jun 10;44(7):751-9. doi: 10.1038/ng.2323.
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.
肾细胞癌（RCC）的分子发病机制尚不清楚。全基因组和外显子组测序，然后进行创新的肿瘤移植分析（以准确确定突变等位基因比例），确定了几个可能的双打击肿瘤抑制基因，包括 BAP1。BAP1 蛋白是一种核去泛素化酶，在 15%的透明细胞 RCC 中失活。BAP1 在肿瘤移植中与 HCF-1 共分馏并结合。破坏 HCF-1 结合基序的突变会损害 BAP1 介导的细胞增殖抑制作用，但不会影响单泛素化组蛋白 H2A 赖氨酸 119（H2AK119ub1）的去泛素化。BAP1 缺失使体外 RCC 细胞对遗传毒性应激敏感。值得注意的是，BAP1 和 PBRM1 中的突变在肿瘤中呈负相关（P = 3 × 10(-5)），[更正]并且少数 RCC 中 BAP1 和 PBRM1 的联合缺失与横纹肌样特征相关（q = 0.0007）。BAP1 和 PBRM1 调节看似不同的基因表达程序，BAP1 缺失与高肿瘤分级相关（q = 0.0005）。我们的研究结果为 RCC 的综合病理和分子遗传分类奠定了基础，为利用遗传脆弱性的特定亚型治疗铺平了道路。
