Alabdullah M L, Ahmad D A, Moseley P, Madhusudan S, Chan S, Rakha E
a Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine , University of Nottingham , Nottingham , UK.
b Paediatric Surgery Department , Birmingham Children's Hospital NHS Trust , Birmingham , UK.
J Obstet Gynaecol. 2019 May;39(4):522-528. doi: 10.1080/01443615.2018.1534091. Epub 2019 Feb 4.
Ovarian cancer is associated with the highest mortality rate among gynaecologic malignancies. There is a need to refine the classification of ovarian cancer and identify novel targets. The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. This study aims to investigate the prognostic role of p-mTOR and its major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer. p-mTOR, p-4EBP1 and p-P70S6K protein expression was assessed on 195 consecutive ovarian epithelial cancers and correlated to clinicopathological features and survival. We found that high cytoplasmic expression of p-4EBP1 and p-P70S6K was associated with a serous type carcinoma (p = .005) and an advanced FIGO stage (p = .012), respectively. Univariate outcome analysis showed an inverse association between a high expression of p-4EBP1 expression and overall ovarian cancer survival (OS; p = .005) and progression-free survival (PFS; p = .005). p-P70S6K showed an inverse association with PFS (p = .001). Multivariate analyses indicated that p-4EBP1 was an independent predictor of both OS and PFS (p = .016 and p = .041, respectively). Therefore, we concluded that p-4EBP1 high protein expression is an independent predictor of outcome in ovarian cancer patients. Therefore, it could be used as a potential biomarker for prognostic stratification and treatment decisions. Impact statement What is already known on this subject? The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. To-date, very limited knowledge is known about the importance of mTOR major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer. What do the results of this study add? In this study, we have provided further evidence of the adverse prognostic behaviour associated with the positive expression of p-mTOR and its major downstream effectors. Moreover and by performing multivariate analysis, we for the first time have proved that p-4EBP1 is an independent predictor of clinical outcome in ovarian cancer. What are the implications of these findings for clinical practice and/or further research? p-4EBP1 could be used as a potential biomarker for prognostic stratification and treatment decisions in ovarian cancer management.
卵巢癌是妇科恶性肿瘤中死亡率最高的。有必要完善卵巢癌的分类并确定新的靶点。雷帕霉素哺乳动物靶点（mTOR）通路在卵巢癌的发病机制和进展中起关键作用。本研究旨在探讨磷酸化mTOR（p-mTOR）及其主要下游效应分子磷酸化真核翻译起始因子4E结合蛋白1（p-4EBP1）和磷酸化核糖体蛋白S6激酶（p-P70S6K）在卵巢癌中的预后作用。对195例连续的卵巢上皮癌患者评估p-mTOR、p-4EBP1和p-P70S6K蛋白表达，并将其与临床病理特征及生存情况相关联。我们发现，p-4EBP1和p-P70S6K的高细胞质表达分别与浆液性癌（p = 0.005）和国际妇产科联盟（FIGO）晚期（p = 0.012）相关。单因素生存分析显示，p-4EBP1高表达与卵巢癌总生存期（OS；p = 0.005）和无进展生存期（PFS；p = 0.005）呈负相关。p-P70S6K与PFS呈负相关（p = 0.001）。多因素分析表明，p-4EBP1是OS和PFS的独立预测因子（分别为p = 0.016和p = 0.041）。因此，我们得出结论，p-4EBP1高蛋白表达是卵巢癌患者预后的独立预测因子。因此，它可作为预后分层和治疗决策的潜在生物标志物。影响声明关于该主题已了解哪些内容？雷帕霉素哺乳动物靶点（mTOR）通路在卵巢癌的发病机制和进展中起关键作用。迄今为止，关于mTOR主要下游效应分子p-4EBP1（真核翻译起始因子4E结合蛋白1）和p-P70S6K（核糖体蛋白S6激酶）在卵巢癌中的重要性了解非常有限。本研究结果有何新发现？在本研究中，我们进一步证明了p-mTOR及其主要下游效应分子阳性表达与不良预后行为相关。此外，通过多因素分析，我们首次证明p-4EBP1是卵巢癌临床结局的独立预测因子。这些发现对临床实践和/或进一步研究有何意义？p-4EBP1可作为卵巢癌管理中预后分层和治疗决策的潜在生物标志物。
