Diagnostic Biomarker Discovery Laboratory, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, 5 Lower Kent Ridge Road, 119074, Singapore.
BMC Cancer. 2010 Feb 24;10:64. doi: 10.1186/1471-2407-10-64.
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.
卵巢上皮性癌（OEC）通常在疾病晚期出现。影响卵巢癌发生和肿瘤进展的因素，特别是与细胞周期基因相关的因素，在很大程度上尚不清楚。我们假设，过度表达的转录因子（TFs）以及驱动 OEC 过度表达基因表达的 TFs，可能是 OEC 发生的关键，并且可能是与 OEC 相关的恶性肿瘤有用的组织和血清标志物。
我们使用计算（候选 TF 标志物的选择和恶性肿瘤预测）和实验方法（患者样本的组织微阵列和 Western 印迹）相结合的方法，鉴定并评估了参与细胞增殖的 E2F5 转录因子，作为早期疾病中具有前景的候选调控靶点。我们的组织阵列实验表明，E2F5 仅在 OEC 样本中表达，而不在正常和良性组织中表达，Western 印迹研究也显示 E2F5 在血清样本中呈明显正偏表达，这支持了我们的假设。
对临床病例的分析表明，E2F5 状态与 CA125 这一传统的 OEC 生物标志物所涵盖的人群不同。E2F5 与 CA125 联合用于区分恶性囊肿与良性囊肿，结果表明，CA125 或 E2F5 的存在可将 OEC 的检测敏感性提高到 97.9%（如果仅使用 CA125，则敏感性从 87.5%提高），更重要的是，CA125 和 E2F5 同时存在可将 OEC 的特异性提高到 72.5%（如果仅使用 CA125，则特异性从 55%提高）。这一显著提高的准确性表明，OEC 的诊断可能得到改善。此外，对 86 例病例（38 例良性，48 例早期和晚期 OEC）的恶性状态检测表明，E2F5 状态与其他临床特征相结合的使用可将恶性病例的检测敏感性、特异性、F 度量和准确性分别提高到 97.92%、97.37%、97.92%和 97.67%。
总之，我们的研究结果除了为 OEC 诊断的改善提供了现实可能性之外，还间接表明细胞周期调节蛋白 E2F5 可能在 OEC 发病机制中发挥重要作用。
