E2F4 Program Is Predictive of Progression and Intravesical Immunotherapy Efficacy in Bladder Cancer.
E2F4 Program Is Predictive of Progression and Intravesical Immunotherapy Efficacy in Bladder Cancer.
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DOI：
10.1158/1541-7786.mcr-15-0120
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Marsit CJ
中科院分区：
文献类型：
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作者：
Cheng C;Varn FS;Marsit CJ
膀胱癌是一种常见的恶性肿瘤，其中非肌层浸润性膀胱癌（NMIBC）占大多数肿瘤。这种癌症亚型通常通过经尿道切除术治疗。尽管治疗，高达70%的患者显示局部复发。膀胱内BCG（卡介苗）免疫疗法已被广泛用于治疗NMIBC，但它未能抑制高达40%的患者膀胱肿瘤复发。因此，需要发展预后标志物来预测膀胱癌的进展和膀胱内BCG治疗的疗效。这项研究证明了E2 F4标记对膀胱癌预后预测的有效性。通过总结ChIP-seq鉴定的E2 F4靶基因的相对表达水平，计算膀胱癌表达数据集中每个样本的E2 F4评分，然后将评分用于将患者分为良好和不良结局组。在单个膀胱癌数据集中研究了分子特征，然后在由来自多个独立研究的标本组成的两个元膀胱数据集中证实了其有效性。这些结果在不同的数据集中是一致的，并且表明E2 F4评分预测膀胱癌的临床结果，在非肌肉浸润性和肌肉浸润性膀胱癌中，肿瘤表现出E2 F4评分>0的患者的存活时间显著短于E2 F4评分<0的患者。此外，尽管膀胱内BCG免疫治疗可以显著改善E2 F4评分阳性（E2 F4>0组）的NMIBC患者的临床结局，但对于那些评分阴性（E2 F4 <0组）的患者，其没有显示出显著的治疗效果。E2 F4标记可用于预测膀胱癌的进展/复发和患者对膀胱内BCG免疫治疗的反应性。
Bladder cancer is a common malignant disease, with non–muscle-invasive bladder cancer (NMIBC) representing the majority of tumors. This cancer subtype is typically treated by transurethral resection. In spite of treatment, up to 70% of patients show local recurrences. Intravesical BCG (Bacillus Calmette-Guerin) immunotherapy has been widely used to treat NMIBC, but it fails to suppress recurrence of bladder tumors in up to 40% of patients. Therefore, the development of prognostic markers is needed to predict the progression of bladder cancer and the efficacy of intravesical BCG treatment. This study demonstrates the effectiveness of an E2F4 signature for prognostic prediction of bladder cancer. E2F4 scores for each sample in a bladder cancer expression dataset were calculated by summarizing the relative expression levels of E2F4 target genes identified by ChIP-seq, and then the scores were used to stratify patients into good- and poor-outcome groups. The molecular signature was investigated in a single bladder cancer dataset and then its effectiveness was confirmed in two meta-bladder datasets consisting of specimens from multiple independent studies. These results were consistent in different datasets and demonstrate that the E2F4 score is predictive of clinical outcomes in bladder cancer, with patients whose tumors exhibit an E2F4 score >0 having significantly shorter survival times than those with an E2F4 score <0, in both non–muscle-invasive, and muscle-invasive bladder cancer. Furthermore, although intravesical BCG immunotherapy can significantly improve the clinical outcome of NMIBC patients with positive E2F4 scores (E2F4>0 group), it does not show significant treatment effect for those with negative scores (E2F4<0 group). The E2F4 signature can be applied to predict the progression/recurrence and the responsiveness of patients to intravesical BCG immunotherapy in bladder cancer.