Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Genes Chromosomes Cancer. 2011 Jun;50(6):397-408. doi: 10.1002/gcc.20864. Epub 2011 Mar 15.
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 ∼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.
小儿横纹肌肉瘤（Rhabdomyosarcoma）有两种生物学上明显不同的组织学变异型，即胚胎型（embryonal，ERMS）和肺泡型（alveolar，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（array comparative genomic hybridization，aCGH）平台，来检测一组特定的 ERMS 肿瘤，这些肿瘤发生在具有临床定义的中危疾病的儿童中。所使用的 aCGH 平台的平均探针间距约为 1 kb，并且可以鉴定出具有单个基因分辨率的基因组变化。我们的数据表明，这些肿瘤共享一个共同的基因组程序，包括 p53 和 Rb 通路的主调控因子 CDKN2A/B 的失活，以及 FGFR4、Ras 和 Hedgehog（Hh）信号通路的激活。CDKN2A/B 肿瘤抑制基因在大多数患者样本中缺失。FGFR4 编码一种受体酪氨酸激酶，在 20%的肿瘤中被激活，主要是通过扩增突变的、激活的 FGFR4 等位基因。超过 50%的患者有包含 Hh 通路转录因子 GLI1 的低水平增益区域，并且存在与 Hh 通路激活一致的基因表达模式。我们还在 15%的肿瘤样本中鉴定出影响 NF1 的基因内缺失，NF1 是一种肿瘤抑制因子和 Ras 的抑制剂。NF1 的缺失和 Ras 激活突变的存在（在 42%的患者中）是相互排斥的，这表明 NF1 缺失是 ERMS 中 Ras 激活的另一种潜在常见机制。我们的数据表明，中危 ERMS 是由一组共同的基因组缺陷驱动的，这一发现对应用靶向治疗来改善诊断为这种疾病的儿童的治疗具有重要意义。
