Global gene expression profiling of PAX-FKHR fusion-positive alveolar and PAX-FKHR fusion-negative embryonal rhabdomyosarcomas
Global gene expression profiling of PAX-FKHR fusion-positive alveolar and PAX-FKHR fusion-negative embryonal rhabdomyosarcomas
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DOI：
10.1002/path.2170
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发表时间：
2007-06-01
影响因子：
7.3
通讯作者：
Ladanyi, M.
中科院分区：
文献类型：
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作者：
Lae, M.;Ahn, E. H.;Ladanyi, M.
小儿横纹肌肉瘤（RMS）根据组织学表现分为两种主要亚型，胚胎型（ERMS）和肺泡型（ARMS），但仅从形态学角度往往难以进行临床上的关键区分。ARMS是一种更具侵袭性的亚型，在大多数情况下与独特的复发性易位相关，该易位将PAX 3或PAX 7转录因子基因融合到FKHR。相比之下，ERMS缺乏独特的遗传改变。为了鉴定新的诊断标志物和潜在的治疗靶点，我们使用Affytelium HG-U133 A寡核苷酸阵列分析了23例ARMS（16例PAX 3-FKHR，7例PAX 7-FKHR）和15例ERMS（均为PAX-FKHR阴性）中这两种RMS亚型的全局基因表达谱。ARMS和ERMS表达谱的统计学严格监督比较揭示了121个显著差异表达的基因，其中112个在ARMS中更高，包括潜在的感兴趣的基因，如CNR 1、PIPOX（肌氨酸氧化酶）和诊断标记物或治疗靶点TFAP β。有趣的是，许多已知或推定的PAX 3-FKHR下游靶标在ARMS中相对于ERMS高度过表达，包括CNR 1、DCX、ABAT、ASS、JAKMIP 2、DKFZp 762 M127和NRCAM。我们验证了五个基因的高度差异表达，包括CNR 1，DIFZp 762 M127，DCX，PIPOX，和FOXF 1在ARMS相对于ERMS通过定量RT-PCR在一组独立的样品。最后，我们开发了一种基于十个基因的微阵列预测器，该预测器通过交叉验证和使用26个样本的已发表数据集进行的独立验证，将ARMS与ERMS区分开来，准确率约为95%。ARMS的基因表达特征提供了潜在的诊断标志物、治疗靶点和PAX-FKHR下游基因的来源，并可用于可靠地区分这些肉瘤和ERMS。版权所有（c）2007大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Paediatric rhabdomyosarcomas (RMS) are classified into two major subtypes based on histological appearance, embryonal (ERMS) and alveolar (ARMS), but this clinically critical distinction is often difficult on morphological grounds alone. ARMS, the more aggressive subtype, is associated in most cases with unique recurrent translocations fusing the PAX3 or PAX7 transcription factor genes to FKHR. In contrast, ERMS lacks unique genetic alterations. To identify novel diagnostic markers and potential therapeutic targets, we analysed the global gene expression profiles of these two RMS subtypes in 23 ARMS (16 PAX3-FKHR, 7 PAX7-FKHR) and 15 ERMS (all PAX-FKHR-negative) using Affymetrix HG-U133A oligonucleotide arrays. A statistically stringent supervised comparison of the ARMS and ERMS expression profiles revealed 121 genes that were significantly differentially expressed, of which 112 were higher in ARMS, including genes of interest as potential such as CNR1, PIPOX (sarcosine oxidase), and diagnostic markers or therapeutic targets,, TFAP beta. Interestingly, many known or putative downstream targets of PAX3-FKHR were highly overexpressed in ARMS relative to ERMS, including CNR1, DCX, ABAT, ASS, JAKMIP2, DKFZp762M127, and NRCAM. We validated the highly differential expression of five genes, including CNR1, DI FZp762M127, DCX, PIPOX, and FOXF1 in ARMS relative to ERMS by quantitative RT-PCR on an independent set of samples. Finally, we developed a ten-gene microarray-based predictor that distinguished ARMS from ERMS with approximately 95% accuracy both in our data by cross-validation and in an independent validation using a published dataset of 26 samples. The gene expression signature of ARMS provides a source of potential diagnostic markers, therapeutic targets, and PAX-FKHR downstream genes, and can be used to reliably distinguish these sarcomas from ERMS. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.