Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Nat Genet. 2011 Jun 5;43(7):668-72. doi: 10.1038/ng.855.
Malignant pleural mesotheliomas (MPMs) often show CDKN2A and NF2 inactivation, but other highly recurrent mutations have not been described. To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPMs. The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes. These findings implicate transcriptional deregulation in the pathogenesis of MPM.
恶性胸膜间皮瘤（MPMs）通常表现出 CDKN2A 和 NF2 的失活，但尚未描述其他高频复发的突变。为了鉴定其他驱动基因，我们对 53 个 MPM 肿瘤样本进行了综合基因组分析，以指导聚焦测序工作，发现 23%的 MPM 中存在 BAP1 的体细胞失活突变。BAP1 核去泛素化酶已知靶向组蛋白（与 ASXL1 作为 Polycomb 抑制亚基一起）和 HCF1 转录共因子，我们表明 BAP1 在 MPM 细胞系中的敲低会影响 E2F 和 Polycomb 靶基因。这些发现提示转录失调参与了 MPM 的发病机制。
