Department of Medical Oncology, Erasmus MC-JNI-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Gynecol Oncol. 2010 May;117(2):170-6. doi: 10.1016/j.ygyno.2010.01.010. Epub 2010 Feb 4.
Ovarian cancer is the leading cause of death from gynecological cancers in the Western world (Parkin et al., 2005). The overall 5-year survival is only 30% (Moss and Kaye, 2002), which is for a significant part due to platinum-based chemotherapy resistance. In this study, we performed a pathway analysis on nine published gene sets associated with platinum resistance in ovarian cancer, including a study by us. With this exploratory study, we aim to identify overlapping pathways associated with platinum-based chemotherapy resistance mechanisms in ovarian cancer.
Gene Ontology (GO) analysis and Ingenuity Pathway Analysis (IPA) were performed to determine which functional processes were differentially represented in the combined gene lists of nine studies (457 genes) compared to all Unigene identifiers or the Ingenuity knowledge base.
The GO and IPA analysis resulted in the generation of 23 gene networks, and showed that 13 GO processes (>or=2 times enriched), 71 canonical pathways (p<0.05,), eight toxicity pathways (p<0.05) and 74 biological functions (p<0.005) are significantly associated with the 9-study gene set.
Several pathways identified have previously been shown to be associated with therapy resistance: these include 'oxidative stress response mediated by Nrf2,' 'TP53 signaling' and 'TGFbeta signaling.' The role of TGFbeta signaling and related miRNAs identified in the network analysis in epithelial-to-mesenchymal transition (EMT) and stemness as well as the possible relation with platin-based chemotherapy resistance are further discussed in detail. We propose that future international cooperation should aim at a uniform pooled analysis of the wealth of ovarian cancer array data already available. This will enhance the power of each separate ovarian cancer study and can lead to promising results.
卵巢癌是西方世界妇科癌症死亡的主要原因（Parkin 等人，2005 年）。整体 5 年生存率仅为 30%（Moss 和 Kaye，2002 年），这在很大程度上是由于铂类化疗耐药。在这项研究中，我们对与卵巢癌铂类耐药相关的九个已发表基因集进行了途径分析，其中包括我们的一项研究。通过这项探索性研究，我们旨在确定与卵巢癌铂类化疗耐药机制相关的重叠途径。
进行了基因本体论（GO）分析和 Ingenuity 途径分析（IPA），以确定与九个研究（457 个基因）的组合基因列表相比，哪些功能过程在所有 Unigene 标识符或 Ingenuity 知识库中差异表达。
GO 和 IPA 分析生成了 23 个基因网络，结果表明 13 个 GO 过程（>或=2 倍富集）、71 个经典途径（p<0.05）、8 个毒性途径（p<0.05）和 74 个生物学功能（p<0.005）与 9 项研究基因集显著相关。
鉴定出的几个途径先前已被证明与治疗耐药性相关：这些途径包括“Nrf2 介导的氧化应激反应”、“TP53 信号转导”和“TGFbeta 信号转导”。网络分析中鉴定的 TGFbeta 信号及其相关 miRNA 在上皮间质转化（EMT）和干性中的作用，以及与基于铂的化疗耐药性的可能关系，将在详细讨论。我们建议未来的国际合作应旨在对现有的丰富卵巢癌数组数据进行统一的 pooled 分析。这将增强每个单独的卵巢癌研究的能力，并可能产生有希望的结果。
