TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.
TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.
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DOI：
10.1158/1078-0432.ccr-17-0413
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发表时间：
2017-11-15
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影响因子：
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通讯作者：
Ellis L
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文献类型：
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作者：
Labbé DP;Sweeney CJ;Brown M;Galbo P;Rosario S;Wadosky KM;Ku SY;Sjöström M;Alshalalfa M;Erho N;Davicioni E;Karnes RJ;Schaeffer EM;Jenkins RB;Den RB;Ross AE;Bowden M;Huang Y;Gray KP;Feng FY;Spratt DE;Goodrich DW;Eng KH;Ellis L
目前的临床参数不能将惰性前列腺癌与侵袭性前列腺癌(PCa)区分开来。侵袭性前列腺癌是大多数前列腺癌相关死亡的原因，侵袭性前列腺癌的定义是从局部疾病到转移的进展。最近的基因表达谱被证明在预测PCa患者的预后方面是成功的，然而他们还没有提供靶向治疗方法来抑制患者向转移性疾病的进展。我们总共询问了7个原发PCa队列(N=1,900)、2个抗去势转移的PCA数据集(N=293)和1个预期队列(N=1,385)，以评估TOP2A和EZH2表达对PCa细胞程序和患者预后的影响。我们还对一组原发性前列腺癌患者(N=)进行了TOP2A和EZH2的免疫组织化学染色，结果已知。最后，我们使用新的PCA来源的小鼠细胞系探索了针对TOP2A和EZH2的联合疗法的治疗潜力。我们通过对独立的原发和转移性PCA数据集的全基因组分析证明，TOP2A和EZH2的mRNA和蛋白同时上调适用于疾病更具侵袭性且参与有丝分裂调控的基因显著重叠的原发和转移性患者的子组。重要的是，前列腺癌细胞中的TOP2A和EZH2是关键的癌基因驱动因素，这一事实突出表现在对联合靶向治疗的敏感性上。总体而言，我们的数据支持进一步评估TOP2A和EZH2作为生物标志物，用于早期识别可能受益于辅助或新辅助靶向治疗方法的转移潜能增加的患者。
Current clinical parameters do not stratify indolent from aggressive prostate cancer (PCa). Aggressive PCa, defined by the progression from localized disease to metastasis, is responsible for the majority of PCa-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of PCa patients, however they have yet to provide targeted therapy approaches that could inhibit a patient’s progression to metastatic disease. We have interrogated a total of seven primary PCa cohorts (N = 1,900), two metastatic castration resistant PCa datasets (N = 293) and one prospective cohort (N = 1,385) to assess the impact of TOP2A and EZH2 expression on PCa cellular program and patient outcomes. We also performed immunohistochemical staining for TOP2A and EZH2 in a cohort of primary PCa patients (N = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel PCa-derived murine cell lines. We demonstrate by genome-wide analysis of independent primary and metastatic PCa datasets that concurrent TOP2A and EZH2 mRNA and protein up-regulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in PCa cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Overall, our data supports further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neo-adjuvant targeted therapy approaches.