E2F4 regulatory program predicts patient survival prognosis in breast cancer.
E2F4 regulatory program predicts patient survival prognosis in breast cancer.
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DOI：
10.1186/s13058-014-0486-7
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发表时间：
2014-12-02
期刊：
影响因子：
--
通讯作者：
Cheng C
中科院分区：
文献类型：
--
作者：
Khaleel SS;Andrews EH;Ung M;DiRenzo J;Cheng C
在过去的十年中，遗传和分子特征已被纳入癌症预后预测和治疗决策中，并取得了良好的成功。临床上，这些特征通常用于早期癌症，以评估他们是否需要手术切除后的辅助治疗。在更多临床背景下预测预后的分子特征将是对当前特征的有用补充。我们基于多个组织中共享的靶基因，定义了无处不在的组织因子E2F4的特征。这些靶基因通过染色质免疫沉淀测序（ChIP-seq）实验用概率方法鉴定。然后，我们计算了E2F4在癌症组织中的调节活性评分（RAS），并研究了E2F4 RAS与患者生存的关系。与随机选择的基因相比，我们的E2F4特征基因与乳腺癌患者生存时间相关的可能性高出21倍。使用包含1900多个独特样本的8个独立的乳腺癌数据集，我们将患者分为低E2F4 RAS组和高E2F4 RAS组。E2F4活性分层可高度预测患者预后，即使在控制患者年龄、肿瘤大小、分级、雌激素受体（ER）状态、淋巴结（LN）状态、患者是否接受辅助治疗以及患者的其他预后指标(如佐剂！以及诺丁汉预后指数得分。此外，E2F4 RAS阳性样本的比例在不同的内在乳腺癌亚型中存在差异，这与这些亚型的不同生存谱相一致。我们定义了一个预后标志，E2F4调节活性评分，并表明它可以显著预测乳腺癌患者的预后，而不考虑治疗状态和许多其他临床病理变量的状态。它可以与其他乳腺癌分类方法（如Oncotype DX）结合使用，以改善临床结果预测。本文的在线版本（doi:10.1186/s13058-014-0486-7）包含补充材料，可供授权用户使用。
Genetic and molecular signatures have been incorporated into cancer prognosis prediction and treatment decisions with good success over the past decade. Clinically, these signatures are usually used in early-stage cancers to evaluate whether they require adjuvant therapy following surgical resection. A molecular signature that is prognostic across more clinical contexts would be a useful addition to current signatures. We defined a signature for the ubiquitous tissue factor, E2F4, based on its shared target genes in multiple tissues. These target genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) experiments using a probabilistic method. We then computationally calculated the regulatory activity score (RAS) of E2F4 in cancer tissues, and examined how E2F4 RAS correlates with patient survival. Genes in our E2F4 signature were 21-fold more likely to be correlated with breast cancer patient survival time compared to randomly selected genes. Using eight independent breast cancer datasets containing over 1,900 unique samples, we stratified patients into low and high E2F4 RAS groups. E2F4 activity stratification was highly predictive of patient outcome, and our results remained robust even when controlling for many factors including patient age, tumor size, grade, estrogen receptor (ER) status, lymph node (LN) status, whether the patient received adjuvant therapy, and the patient’s other prognostic indices such as Adjuvant! and the Nottingham Prognostic Index scores. Furthermore, the fractions of samples with positive E2F4 RAS vary in different intrinsic breast cancer subtypes, consistent with the different survival profiles of these subtypes. We defined a prognostic signature, the E2F4 regulatory activity score, and showed it to be significantly predictive of patient outcome in breast cancer regardless of treatment status and the states of many other clinicopathological variables. It can be used in conjunction with other breast cancer classification methods such as Oncotype DX to improve clinical outcome prediction. The online version of this article (doi:10.1186/s13058-014-0486-7) contains supplementary material, which is available to authorized users.
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