Candidate Genes on Chromosome 9q33-34 Involved in the Progression of Childhood Ependymomas
Candidate Genes on Chromosome 9q33-34 Involved in the Progression of Childhood Ependymomas
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DOI：
10.1200/jco.2007.15.4195
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发表时间：
2009-04-10
影响因子：
45.3
通讯作者：
Vassal, Gilles
中科院分区：
文献类型：
--
作者：
Puget, Stephanie;Grill, Jacques;Vassal, Gilles
目的小儿室管膜瘤的分子发病机制尚不清楚。我们的研究旨在确定牵连室管膜瘤progression.Patients和MethodsWe的特点是59室管膜瘤样本（33在诊断和26复发）使用阵列比较基因组杂交（aCGH）的遗传变化。结果CGH分析显示，与诊断结果相比，复发患者的基因组失衡显著增加，如9 qter和1 q的增加（分别为54%对21%和12%对0%）和6 q缺失（27%对6%）。监督肿瘤分类显示，9 qter的增加与肿瘤复发、年龄大于3岁和后颅窝位置相关。使用候选基因策略，我们发现了两个潜在的癌基因在基因座9 qter的过度表达：Tenascin-C和Notch 1。此外，Notch途径分析（qPCR）揭示Notch配体、受体和靶基因（Hes-1、Hey 2和c-Myc）的过表达，以及Notch阻遏物Fbxw 7的下调。我们通过免疫组织化学证实了Tenascin-C和Hes-1的过度表达。我们在8.3%的肿瘤中检测到Notch 1错义突变（仅在后颅窝位置和9 q33 -34增益的情况下）。此外，抑制Notch通路与γ-分泌酶抑制剂损害室管膜瘤干细胞culture.ConclusionThe激活的Notch通路和Tenascin-C的生长似乎是重要的事件室管膜瘤的进展，并可能代表未来的治疗目标。据我们所知，我们首次报道了儿童后颅窝室管膜瘤的复发性致癌基因突变。
PurposeThe molecular pathogenesis of pediatric ependymoma remains unclear. Our study was designed to identify genetic changes implicated in ependymoma progression.Patients and MethodsWe characterized 59 ependymoma samples (33 at diagnosis and 26 at relapse) using array-comparative genomic hybridization (aCGH). Specific chromosomal imbalances were confirmed by fluorescent in situ hybridization, and candidate genes were assessed by real-time quantitative polymerase chain reaction (qPCR), immunohistochemistry, sequencing, and in vitro functional studies.ResultsaCGH analysis revealed a significant increase in genomic imbalances on relapse compared with diagnosis, such as gain of 9qter and 1q (54% v 21% and 12% v 0%, respectively) and loss of 6q (27% v 6%). Supervised tumor classification showed that gain of 9qter was associated with tumor recurrence, age older than 3 years, and posterior fossa location. Using a candidate-gene strategy, we found an overexpression of two potential oncogenes at the locus 9qter: Tenascin-C and Notch1. Moreover, Notch pathway analysis (qPCR) revealed overexpression of Notch ligands, receptors, and target genes (Hes-1, Hey2, and c-Myc), and downregulation of Notch repressor Fbxw7. We confirmed by immunohistochemistry the overexpression of Tenascin-C and Hes-1. We detected Notch1 missense mutations in 8.3% of the tumors (only in the posterior fossa location and in case of 9q33-34 gain). Furthermore, inhibition of Notch pathway with a gamma-secretase inhibitor impaired the growth of ependymoma stem cell cultures.ConclusionThe activation of the Notch pathway and Tenascin-C seem to be important events in ependymoma progression and may represent future targets for therapy. We report, to our knowledge for the first time, recurrent oncogenic mutations in pediatric posterior fossa ependymomas.