Widespread dysregulation of MiRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival.
Widespread dysregulation of MiRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival.
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DOI：
10.1371/journal.pone.0007850
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发表时间：
2009-11-16
期刊：
影响因子：
3.7
通讯作者：
Stallings RL
中科院分区：
文献类型：
--
作者：
Bray I;Bryan K;Prenter S;Buckley PG;Foley NH;Murphy DM;Alcock L;Mestdagh P;Vandesompele J;Speleman F;London WB;McGrady PW;Higgins DG;O'Meara A;O'Sullivan M;Stallings RL
miRNA 在转录后水平调节基因表达，它们的失调在许多不同形式的癌症的发病机制中发挥着重要作用，包括神经母细胞瘤，一种源自交感神经系统前体细胞的通常致命的儿科癌症。我们分析了一组广泛代表该疾病遗传亚型的神经母细胞瘤 (n = 145) 的 miRNA 表达（通过茎环 RT qPCR 检测 430 个位点）和 DNA 拷贝数改变（阵列 CGH），以评估 miRNA 在疾病发病机制中的参与情况。将肿瘤分层，然后随机分为训练集（n = 96）和验证集（n = 49）进行数据分析。相对于 MYCN 单拷贝肿瘤，37 个 miRNA 在 MYCN 扩增肿瘤中显着过度表达或表达不足，表明 MYCN 转录因子在这些位点的直接或间接失调中具有潜在作用。此外，我们还确定 miRNA 表达水平和 DNA 拷贝数之间存在高度显着的相关性，表明大规模基因组失衡在 miRNA 表达失调中发挥了作用。为了直接评估 miRNA 表达是否可以预测临床结果，我们使用随机森林分类器来识别与患者总体生存率差最显着相关的 miRNA，并开发了 15 个 miRNA 特征，该特征在肿瘤验证集中具有 72.7% 的敏感性和 86.5% 的特异性，可以预测总体生存率。我们得出的结论是，神经母细胞瘤中存在广泛的 miRNA 表达失调，这是由 MYCN 转录因子的过度表达和大规模染色体失衡引起的。 miRNA 表达模式还可预测临床结果，凸显 miRNA 介导的诊断和治疗的潜力。
MiRNAs regulate gene expression at a post-transcriptional level and their dysregulation can play major roles in the pathogenesis of many different forms of cancer, including neuroblastoma, an often fatal paediatric cancer originating from precursor cells of the sympathetic nervous system. We have analyzed a set of neuroblastoma (n = 145) that is broadly representative of the genetic subtypes of this disease for miRNA expression (430 loci by stem-loop RT qPCR) and for DNA copy number alterations (array CGH) to assess miRNA involvement in disease pathogenesis. The tumors were stratified and then randomly split into a training set (n = 96) and a validation set (n = 49) for data analysis. Thirty-seven miRNAs were significantly over- or under-expressed in MYCN amplified tumors relative to MYCN single copy tumors, indicating a potential role for the MYCN transcription factor in either the direct or indirect dysregulation of these loci. In addition, we also determined that there was a highly significant correlation between miRNA expression levels and DNA copy number, indicating a role for large-scale genomic imbalances in the dysregulation of miRNA expression. In order to directly assess whether miRNA expression was predictive of clinical outcome, we used the Random Forest classifier to identify miRNAs that were most significantly associated with poor overall patient survival and developed a 15 miRNA signature that was predictive of overall survival with 72.7% sensitivity and 86.5% specificity in the validation set of tumors. We conclude that there is widespread dysregulation of miRNA expression in neuroblastoma tumors caused by both over-expression of the MYCN transcription factor and by large-scale chromosomal imbalances. MiRNA expression patterns are also predicative of clinical outcome, highlighting the potential for miRNA mediated diagnostics and therapeutics.
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DOI：
10.1073/pnas.0801615105
发表时间：
2008-05-13
影响因子：
11.1
作者：
Zhang, Lin;Volinia, Stefano;Coukos, George
通讯作者：
Coukos, George
影响因子：
56.9
作者：
BRODEUR, GM;SEEGER, RC;BISHOP, JM
通讯作者：
BISHOP, JM
影响因子：
30.8
作者：
Chang, Tsung-Cheng;Yu, Duonan;Mendell, Joshua T.
通讯作者：
Mendell, Joshua T.
影响因子：
158.5
作者：
Attiyeh, EF;London, WB;Maris, JM
通讯作者：
Maris, JM
影响因子：
12.3
作者：
Mestdagh P;Van Vlierberghe P;De Weer A;Muth D;Westermann F;Speleman F;Vandesompele J
通讯作者：
Vandesompele J