The mutational landscape of lethal castration-resistant prostate cancer.
The mutational landscape of lethal castration-resistant prostate cancer.
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DOI：
10.1038/nature11125
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发表时间：
2012-07-12
期刊：
影响因子：
64.8
通讯作者：
Tomlins, Scott A.
中科院分区：
文献类型：
--
作者：
Grasso, Catherine S.;Wu, Yi-Mi;Robinson, Dan R.;Cao, Xuhong;Dhanasekaran, Saravana M.;Khan, Amjad P.;Quist, Michael J.;Jing, Xiaojun;Lonigro, Robert J.;Brenner, J. Chad;Asangani, Irfan A.;Ateeq, Bushra;Chun, Sang Y.;Siddiqui, Javed;Sam, Lee;Anstett, Matt;Mehra, Rohit;Prensner, John R.;Palanisamy, Nallasivam;Ryslik, Gregory A.;Vandin, Fabio;Raphael, Benjamin J.;Kunju, Lakshmi P.;Rhodes, Daniel R.;Pienta, Kenneth J.;Chinnaiyan, Arul M.;Tomlins, Scott A.
前列腺癌转录组和基因组的表征已经确定了染色体重排和拷贝数增加/减少，包括ETS基因融合、PTEN丢失和雄激素受体（AR）扩增，其驱动前列腺癌发展和进展为致死性、转移性去势抵抗性前列腺癌（CRPC）。由于对突变的作用知之甚少，在这里，我们对快速尸检中获得的50个致命的，经过大量预处理的转移性CRPC（包括来自同一患者的三个不同病灶）和11个未经治疗的，高级别局部前列腺癌的外显子组进行了测序。我们发现，即使在重度治疗的CRPC中，总体突变率也较低（2.00/Mb），并证实了致死性CRPC的单克隆起源。整合外显子组拷贝数分析鉴定了CHD 1的破坏，其定义了ETS融合阴性前列腺癌的亚型。类似地，我们证明了在约1/3的CRPC中缺失的ETS 2（通常通过TMPRSS 2：ERG融合）也通过突变而失调。此外，我们确定了多个染色质/组蛋白修饰基因中的复发性突变，包括MLL 2（在8.6%的前列腺癌中突变），并证明了MLL复合物与AR的相互作用，这是AR介导的信号传导所必需的。我们还鉴定了AR协作因子FOXA 1中的新复发突变，该因子在147例前列腺癌中的5例（3.4%）中发生突变（未经治疗的局限性前列腺癌和CRPC），并表明突变的FOXA 1抑制雄激素信号传导并增加肿瘤生长。发现与AR物理相互作用的蛋白质，例如ERG基因融合产物、FOXA 1、MLL 2、UTX和ASXL 1在CRPC中发生突变。总之，我们描述了大量治疗转移性癌症的突变景观，确定了前列腺癌中AR信号失调的新机制，并优先考虑未来研究的候选人。
Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC). As less is known about the role of mutations, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS fusionnegative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR-mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signaling and increases tumour growth. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study.
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影响因子：
50.3
作者：
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作者：
Gao, N;Zhang, JF;Matusik, RJ
通讯作者：
Matusik, RJ