High-Resolution Array CGH Identifies Common Mechanisms that Drive Embryonal Rhabdomyosarcoma Pathogenesis
High-Resolution Array CGH Identifies Common Mechanisms that Drive Embryonal Rhabdomyosarcoma Pathogenesis
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DOI：
10.1002/gcc.20864
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发表时间：
2011-06-01
影响因子：
3.7
通讯作者：
Cameron, Scott
中科院分区：
文献类型：
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作者：
Paulson, Vera;Chandler, Garvin;Cameron, Scott
儿童横纹肌肉瘤有两种不同的生物学特征，胚胎型(ERMS)和肺泡型(ARMS)。为了确定驱动ERMS发病机制的基因组变化，我们使用了一种新的阵列比较基因组杂交(ACGH)平台来检查ERMS肿瘤的特定子集，这些肿瘤发生在患有临床定义的中等风险疾病的儿童中。所用的aCGH平台的平均探针间距接近1kb，可以单基因分辨率识别基因组变化。我们的数据表明，这些肿瘤共享一个共同的基因组计划，包括P53和RB通路的主要调节因子CDKN2A/B的失活，以及FGFR4、RAS和Hedgehog(HH)信号的激活。CDKN2A/B肿瘤抑制基因在大多数患者样本中缺失。编码受体酪氨酸激酶的FGFR4在20%的肿瘤中被激活，主要是通过扩增突变的激活FGFR4等位基因。超过50%的患者有包含HH途径转录因子GLI1的区域的低水平增益，以及与HH途径激活一致的基因表达模式。我们还在15%的肿瘤样本中发现了影响NF1的基因内缺失，NF1是一种肿瘤抑制因子和RAS的抑制剂。NF1缺失和RAS激活突变的存在(在42%的患者中)是相互排斥的，提示NF1缺失是ERMS中RAS激活的另一种潜在的常见机制。我们的数据表明，中等风险的ERMS是由一组常见的基因组缺陷驱动的，这一发现对应用靶向治疗以改善被诊断为这种疾病的儿童的治疗具有重要意义。(C)2011年Wiley-Liss，Inc.
Pediatric rhabdomyosarcoma occurs as two biologically distinct histological variants, embryonal (ERMS) and alveolar (ARMS). To identify genomic changes that drive ERMS pathogenesis, we used a new array comparative genomic hybridization (aCGH) platform to examine a specific subset of ERMS tumors, those occurring in children with clinically defined intermediate-risk disease. The aCGH platform used has an average probe spacing similar to 1 kb, and can identify genomic changes with single gene resolution. Our data suggest that these tumors share a common genomic program that includes inactivation of a master regulator of the p53 and Rb pathways, CDKN2A/B, and activation of FGFR4, Ras, and Hedgehog (Hh) signaling. The CDKN2A/B tumor suppressor is deleted in most patient samples. FGFR4, which encodes a receptor tyrosine kinase, is activated in 20% of tumors, predominantly by amplification of mutant, activating FGFR4 alleles. Over 50% of patients had low-level gains of a region containing the Hh-pathway transcription factor GLI1, and a gene expression pattern consistent with Hh-pathway activation. We also identified intragenic deletions affecting NF1, a tumor suppressor and inhibitor of Ras, in 15% of tumor samples. Deletion of NF1 and the presence of activating Ras mutations (in 42% of patients) were mutually exclusive, suggesting NF1 loss is an alternative and potentially common mechanism of Ras activation in ERMS. Our data suggest that intermediate-risk ERMS is driven by a common set of genomic defects, a finding that has important implications for the application of targeted therapies to improve the treatment of children diagnosed with this disease. (C) 2011 Wiley-Liss, Inc.