E2F5 status significantly improves malignancy diagnosis of epithelial ovarian cancer.
E2F5 status significantly improves malignancy diagnosis of epithelial ovarian cancer.
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DOI：
10.1186/1471-2407-10-64
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发表时间：
2010-02-24
期刊：
影响因子：
3.8
通讯作者：
Choolani M
中科院分区：
文献类型：
--
作者：
Kothandaraman N;Bajic VB;Brendan PN;Huak CY;Keow PB;Razvi K;Salto-Tellez M;Choolani M
卵巢上皮癌（OEC）通常在疾病的晚期出现。影响卵巢癌发生和肿瘤进展的因素，尤其是与细胞周期基因相关的因素，在很大程度上是未知的。我们假设过度表达的转录因子（TFs）以及驱动卵巢上皮癌过度表达基因表达的转录因子可能是卵巢上皮癌发生的关键，并且可能是与卵巢上皮癌相关的恶性肿瘤的有用的组织和血清标志物。
通过结合计算方法（候选转录因子标志物的选择和恶性程度预测）和实验方法（组织微阵列以及对患者样本进行蛋白质印迹分析），我们鉴定并评估了参与细胞增殖的E2F5转录因子，将其作为早期疾病中一个有希望的候选调控靶点。我们的组织阵列实验表明E2F5仅在卵巢上皮癌样本中表达，而在正常和良性组织中不表达，并且通过蛋白质印迹研究发现其在血清样本中的表达具有显著的正向偏向，这些都支持了我们的假设。
临床病例分析表明，E2F5的状态所针对的人群与传统的卵巢上皮癌生物标志物CA125所针对的人群不同。将E2F5与CA125以不同组合用于区分恶性囊肿和良性囊肿时发现，CA125或E2F5的存在使卵巢上皮癌检测的敏感性提高到97.9%（如果仅使用CA125则为87.5%），更重要的是，CA125和E2F5同时存在使卵巢上皮癌检测的特异性提高到72.5%（如果仅使用CA125则为55%）。这种显著提高的准确性表明有可能改进卵巢上皮癌的诊断。此外，对86例病例（38例良性，48例早期和晚期卵巢上皮癌）的恶性程度检测表明，将E2F5状态与其他临床特征相结合，可以提高恶性病例的检测率，其敏感性、特异性、F值和准确性分别为97.92%、97.37%、97.92%和97.67%。
总体而言，我们的研究结果除了为改进卵巢上皮癌的诊断提供了一种现实的可能性外，还间接证明了细胞周期调节蛋白E2F5可能在卵巢上皮癌的发病机制中发挥重要作用。
Ovarian epithelial cancer (OEC) usually presents in the later stages of the disease. Factors, especially those associated with cell-cycle genes, affecting the genesis and tumour progression for ovarian cancer are largely unknown. We hypothesized that over-expressed transcription factors (TFs), as well as those that are driving the expression of the OEC over-expressed genes, could be the key for OEC genesis and potentially useful tissue and serum markers for malignancy associated with OEC. Using a combination of computational (selection of candidate TF markers and malignancy prediction) and experimental approaches (tissue microarray and western blotting on patient samples) we identified and evaluated E2F5 transcription factor involved in cell proliferation, as a promising candidate regulatory target in early stage disease. Our hypothesis was supported by our tissue array experiments that showed E2F5 expression only in OEC samples but not in normal and benign tissues, and by significantly positively biased expression in serum samples done using western blotting studies. Analysis of clinical cases shows that of the E2F5 status is characteristic for a different population group than one covered by CA125, a conventional OEC biomarker. E2F5 used in different combinations with CA125 for distinguishing malignant cyst from benign cyst shows that the presence of CA125 or E2F5 increases sensitivity of OEC detection to 97.9% (an increase from 87.5% if only CA125 is used) and, more importantly, the presence of both CA125 and E2F5 increases specificity of OEC to 72.5% (an increase from 55% if only CA125 is used). This significantly improved accuracy suggests possibility of an improved diagnostics of OEC. Furthermore, detection of malignancy status in 86 cases (38 benign, 48 early and late OEC) shows that the use of E2F5 status in combination with other clinical characteristics allows for an improved detection of malignant cases with sensitivity, specificity, F-measure and accuracy of 97.92%, 97.37%, 97.92% and 97.67%, respectively. Overall, our findings, in addition to opening a realistic possibility for improved OEC diagnosis, provide an indirect evidence that a cell-cycle regulatory protein E2F5 might play a significant role in OEC pathogenesis.