Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer
Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer
复制标题
DOI：
10.1158/0008-5472.can-08-3667
复制
发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
de Bono, Johann S.
中科院分区：
文献类型：
--
作者：
Attard, Gerhardt;Swermenhuis, Joost F.;de Bono, Johann S.
与TMPRSS 2融合后，ERG癌基因的激素驱动表达发生在30%至70%的未经治疗的前列腺癌中。其在去势抵抗性前列腺癌（CRPC）中的相关性仍然存在争议，因为ERG在一些TMPRSS 2-ERG雄激素非依赖性异种移植模型中不表达。然而，与这些模型不同，CRPC患者的前列腺特异性抗原增加，表明雄激素受体信号传导活跃。在这里，我们每月收集89例患者（54例化疗初治患者和35例紫杉醇治疗患者）的血液，这些患者在口服高特异性CYP 17抑制剂醋酸阿比特龙的I期/II期临床试验中接受治疗，醋酸阿比特龙可消除驱动TMPRSS 2-ERG融合的雄激素和雌激素的合成。我们通过抗上皮细胞粘附分子免疫磁性选择，然后通过细胞角蛋白和CD 45免疫荧光和4 '，6-diamidino-2-phenylindole染色分离循环肿瘤细胞（CTC）。我们使用荧光原位杂交显示CRPC CTC、转移瘤和前列腺组织总是具有与未经治疗的肿瘤相同的ERG基因状态（n = 31）。然后，我们使用定量逆转录-PCR显示，ERG表达维持在CRPC。我们还观察到CTC中ERG基因重排状态的同质性（n = 48），而AR拷贝数增加和PTEN丢失的显著异质性相反，这表明ERG重排可能是前列腺癌发生的早期事件。最后，我们报告了未经治疗的肿瘤、CRPC和CTC中的ERG重排与接受醋酸阿比特龙治疗的CRPC患者的前列腺特异性抗原下降幅度（P = 0.007）之间的显著相关性。这些数据证实了CTC是恶性起源的，并表明表达受调控的CTCs是恶性的。
Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC) by anti-epithelial cell adhesion molecule immunomagnetic selection followed by cytokeratin and CD45 immunofluorescence and 4',6diamidino-2-phenylindole staining. We used multicolor fluorescence in situ hybridization to show that CRPC CTCs, metastases, and prostate tissue invariably had the same ERG gene status as therapy-naive tumors (n = 31). We then used quantitative reverse transcription-PCR to show that ERG expression was maintained in CRPC. We also observed homogeneity in ERG gene rearrangement status in CTCs (n = 48) in contrast to significant heterogeneity of AR copy number gain and PTEN loss, suggesting that rearrangement of ERG may be an earlier event in prostate carcinogenesis. We finally report a significant association between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of prostate-specific antigen decline (P = 0.007) in CRPC patients treated with abiraterone acetate. These data confirm that CTCs are malignant in origin and indicate that hormone-regulated expression