High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma.
High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma.
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DOI：
10.1097/jto.0000000000000471
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发表时间：
2015-04
期刊：
影响因子：
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通讯作者：
Carbone M
中科院分区：
文献类型：
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作者：
Nasu M;Emi M;Pastorino S;Tanji M;Powers A;Luk H;Baumann F;Zhang YA;Gazdar A;Kanodia S;Tiirikainen M;Flores E;Gaudino G;Becich MJ;Pass HI;Yang H;Carbone M
BAP1是一种核脱泛素酶，调节基因表达、转录、DNA修复等。一些研究结果强调了BAP1在恶性间皮瘤(MM)中的明显“驱动”作用。然而，在多发性骨髓瘤中报道的体细胞BAP1突变的频率差异很大，这种差异似乎与不同研究中的方法或种族差异有关。为了解决这一差异，我们进行了全面的基因组和免疫组织化学(IHC)分析，以检测来自美国MM患者的22例冷冻MM活检组织中体细胞BAP1基因的变化。结合Sanger测序、多重连接依赖的探针扩增、拷贝数分析和cDNA测序，我们发现14/22例活检组织中BAP1基因发生了改变(63.6%)。没有观察到甲基化的变化。在含有野生型BAP1的8个MM中，免疫组化显示BAP1的核染色正常，而在含有突变的BAP1的14个MM的活检组织中，未检测到核染色。因此，IHC结果与基因组分析的结果是一致的。然后，我们将IHC分析扩展到70例MM活检的独立队列，其中没有足够的材料来进行分子研究。免疫组化显示70例MM组织中47例(67.1%)BAP1核染色缺失。我们的发现最终确定BAP1基因是多发性骨髓瘤中最常见的突变基因，与种族背景或其他临床特征无关。我们的数据表明，免疫组织化学是检测多发性骨髓瘤活检组织中BAP1状态的最易获得和最可靠的技术。
BAP1 is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent “driver” role of BAP1 in malignant mesothelioma (MM). However the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies. To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from US MM patients. By combining Sanger sequencing, Multiplex Ligation-Dependent Probe Amplification, copy number analysis and cDNA sequencing, we found alteration of BAP1 in 14/22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the 8 MM containing wild-type BAP1, while no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 out of these 70 MM biopsies (67.1%). Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies.