Department of Animal Sciences, University of Illinois, Urbana, Illinois, USA.
PLoS One. 2013;8(3):e58608. doi: 10.1371/journal.pone.0058608. Epub 2013 Mar 12.
The identification of reliable transcriptome biomarkers requires the simultaneous consideration of regulatory and target elements including microRNAs (miRNAs), transcription factors (TFs), and target genes. A novel approach that integrates multivariate survival analysis, feature selection, and regulatory network visualization was used to identify reliable biomarkers of ovarian cancer survival and recurrence. Expression profiles of 799 miRNAs, 17,814 TFs and target genes and cohort clinical records on 272 patients diagnosed with ovarian cancer were simultaneously considered and results were validated on an independent group of 146 patients. Three miRNAs (hsa-miR-16, hsa-miR-22*, and ebv-miR-BHRF1-2*) were associated with both ovarian cancer survival and recurrence and 27 miRNAs were associated with either one hazard. Two miRNAs (hsa-miR-521 and hsa-miR-497) were cohort-dependent, while 28 were cohort-independent. This study confirmed 19 miRNAs previously associated with ovarian cancer and identified two miRNAs that have previously been associated with other cancer types. In total, the expression of 838 and 734 target genes and 12 and eight TFs were associated (FDR-adjusted P-value <0.05) with ovarian cancer survival and recurrence, respectively. Functional analysis highlighted the association between cellular and nucleotide metabolic processes and ovarian cancer. The more direct connections and higher centrality of the miRNAs, TFs and target genes in the survival network studied suggest that network-based approaches to prognosticate or predict ovarian cancer survival may be more effective than those for ovarian cancer recurrence. This study demonstrated the feasibility to infer reliable miRNA-TF-target gene networks associated with survival and recurrence of ovarian cancer based on the simultaneous analysis of co-expression profiles and consideration of the clinical characteristics of the patients.
鉴定可靠的转录组生物标志物需要同时考虑调节和靶元件,包括 microRNAs (miRNAs)、转录因子 (TFs) 和靶基因。一种新的方法,整合了多变量生存分析、特征选择和调控网络可视化,用于鉴定卵巢癌生存和复发的可靠生物标志物。同时考虑了 799 个 miRNA、17814 个 TF 和靶基因的表达谱以及 272 名被诊断为卵巢癌的患者的队列临床记录,并在 146 名独立患者的队列中进行了验证。三个 miRNA(hsa-miR-16、hsa-miR-22* 和 ebv-miR-BHRF1-2*)与卵巢癌的生存和复发都有关,27 个 miRNA 与其中一个危险有关。两个 miRNA(hsa-miR-521 和 hsa-miR-497)与队列有关,而 28 个 miRNA 与队列无关。本研究证实了 19 个先前与卵巢癌相关的 miRNA,并确定了两个先前与其他癌症类型相关的 miRNA。总的来说,838 个和 734 个靶基因的表达以及 12 个和 8 个 TF 与卵巢癌的生存和复发相关(FDR 调整的 P 值<0.05)。功能分析突出了细胞和核苷酸代谢过程与卵巢癌之间的关联。在研究的生存网络中,miRNAs、TFs 和靶基因之间的直接连接和更高的中心性表明,基于共表达谱的分析和对患者临床特征的考虑,基于网络的方法预测卵巢癌的生存或复发可能更有效。本研究证明了基于同时分析共表达谱和考虑患者临床特征,推断与卵巢癌生存和复发相关的可靠 miRNA-TF-靶基因网络的可行性。
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