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题目:: Rhabdoid Tumor: Gene Expression Clues to Pathogenesis and Potential Therapeutic Targets
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状态:: 发布时间March 9, 2010 , 更新时间 May 2, 2014 , 提交时间 May 15, 2008,
物种:: Homo sapiens
摘要:: Rhabdoid tumors (RT) are aggressive tumors characterized by genetic loss of SMARCB1 (SNF5, INI-1), a component of the SWI/SNF chromatin remodeling complex. No effective treatment is currently available. This study seeks to shed light on the SMARCB1-mediated pathogenesis of RT and to discover potential therapeutic targets. Global gene expression of 10 RT was compared with 12 cellular mesoblastic nephromas, 16 clear cell sarcomas of the kidney, and 15 Wilms tumors. 114 top genes were differentially expressed in RT (p<0.001, fold change >2 or <0.5). Among these were down-regulation of SMARCB1 and genes previously associated with SMARCB1 (ATP1B1, PTN, DOCK4, NQO1, PLOD1, PTP4A2, PTPRK). 28/114 top differentially expressed genes were involved with neural or neural crest development and were all sharply down-regulated. This was confirmed by Gene Set Enrichment Analysis (GSEA). Neural and neural crest stem cell marker proteins SOX10, ID3, CD133 and Musashi were negative by immunohistochemistry, whereas Nestin was positive. Decreased expression of CDKN1A, CDKN1B, CDKN1C, CDKN2A, and CCND1 was identified, while MYC-C was upregulated. GSEA of independent gene sets associated with bivalent histone modification and polycomb group targets in embryonic stem cells demonstrated significant negative enrichment in RT. Several differentially expressed genes were associated with tumor suppression, invasion and metastasis, including SPP1 (osteopontin), COL18A1 (endostatin), PTPRK, and DOCK4. We conclude that RTs arise within early progenitor cells during a critical developmental window in which loss of SMARCB1 directly results in repression of neural development, loss of cyclin dependent kinase inhibition, and trithorax/polycomb dysregulation. Keywords: Gene expression; rhabdoid tumor; pediatric renal tumors; neural crest The goal of this study is to identify genetic pathways that will clarify the nature of RT and enable the identification of therapeutic targets. Experimental Design: Frozen tissue samples were obtained from the Renal Tumor Bank of the Children's Oncology Group (COG). A total of 53 tumors were hybridized to Affymetrix U133A arrays and analyzed including 10 RT, 12 cellular mesoblastic nephromas (CMN), also known as infantile fibrosarcomas, 16 clear cell sarcomas of the kidney (CCSK) and 15 Wilms tumors (WT). Quality control steps taken: 1. Samples were snap frozen immediately following surgery and were mailed on dry ice to the Tumor Bank and retained at -80°C. 2. Frozen sections were evaluated histologically and tumors with less than 80% viable tumor cellularity were excluded. 3. Array images were assessed by eye to confirm scanner alignment and the absence of significant bubbles or scratches. 4. Samples for which the 3'/5' ratios for GAPDH were greater than 3.4 were excluded. 5. The BioB spike controls were confirmed as present 90% of the time; BioC, BioD and cre were confirmed as increasing intensity in all samples. 6. When scaled to a target intensity of 2500, scaling factors were between 13 and 52; background levels were 34-115: Raw Q values were 1.3-3.7 and mean intensities were within acceptable limits. 7. The range of percent present calls was from 30% to 52%. Statistical Analysis: Positional-dependent-nearest-neighbor model (PDNN) software was used to translate the scanned images into expression analysis files and to normalize the data across all arrays (
实验种类:: transcription profiling by array
样本量:: 53
实验设计:
: 无设计数据
数据号:: E-GEOD-11482, GSE11482
数据状态:: 无法自动分析，您可以尝试手动分析数据。

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