Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer
Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer
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DOI：
10.1158/0008-5472.can-07-6154
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发表时间：
2008-05-15
期刊：
影响因子：
11.2
通讯作者：
Chinnaiyan, Arul M.
中科院分区：
文献类型：
--
作者：
Mehra, Rohit;Tomlins, Scott A.;Chinnaiyan, Arul M.
雄激素调节基因TMPRSS 2和ETS转录因子家族成员ERG、ETV 1和ETV 4之间的复发性基因融合已被确定为前列腺癌发展中的关键事件。在这项研究中，我们描述了这些重排在难治性转移性前列腺癌中的患病率和多样性。我们使用荧光原位杂交（FISH）分裂探针策略，从30例死于雄激素非依赖性疾病的男性快速尸检中，全面评估了97个前列腺癌非骨转移部位的TMPRSS 2-ETS畸变。构建代表每个患者多个转移部位的组织微阵列，并使用TMPRSS 2、ERG、ETV 1和ETV 4的分裂信号FISH探针来评估TMPRSS 2-ETS重排。在表现出这些畸变的患者中，来自单个病例的多个位点具有相同的基因融合分子亚型，表明疾病的克隆扩展。最常见的前列腺癌基因融合体TMPRSS 2-ERG可以在临床局部疾病中约39%至60%的时间通过间质缺失（Edel）机制产生。有趣的是，我们观察到所有含有TMPRSS 2-ERG的雄激素非依赖性转移性前列腺癌位点都与Edel相关。这些发现表明，TMPRSS 2-ERG与Edel是一个积极的，在这项研究中，均匀致命的前列腺癌的分子亚型与雄激素非依赖性疾病。
Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factor family members ERG, ETV1, and ETV4 have been identified as a critical event in prostate cancer development. In this study, we characterized the prevalence and diversity of these rearrangements in hormone-refractory metastatic prostate cancer. We used a fluorescence in situ hybridization (FISH) split probe strategy to comprehensively evaluate TMPRSS2-ETS aberrations across 97 nonosseous metastatic sites of prostate cancer from 30 rapid autopsies of men who died of androgen-independent disease. Tissue microarrays were constructed representing multiple metastatic sites from each patient, and split signal FISH probes for TMPRSS2, ERG, ETV1, and ETV4 were used to assess for TMPRSS2-ETS rearrangements. In patients exhibiting these aberrations, multiple sites from an individual case harbored the same gene fusion molecular subtype suggesting clonal expansion of disease. The most common prostate cancer gene fusion, TMPRSS2-ERG, can be generated by the mechanism of interstitial deletion (Edel) about 39% to 60% of the time in clinically localized disease. Interestingly, we observed that all of the androgen-independent metastatic prostate cancer sites harboring TMPRSS2-ERG were associated with Edel. These findings suggest that TMPRSS2-ERG with Edel is an aggressive and, in this study, uniformly lethal molecular subtype of prostate cancer associated with androgen-independent disease.