Meta-analysis of Neuroblastomas Reveals a Skewed ALK Mutation Spectrum in Tumors with MYCN Amplification
Meta-analysis of Neuroblastomas Reveals a Skewed ALK Mutation Spectrum in Tumors with MYCN Amplification
复制标题
DOI：
10.1158/1078-0432.ccr-09-2660
复制
发表时间：
2010-09-01
影响因子：
11.5
通讯作者：
Speleman, Frank
中科院分区：
文献类型：
--
作者：
De Brouwer, Sara;De Preter, Katleen;Speleman, Frank
目的：最近在神经母细胞瘤中发现了间变性淋巴瘤激酶（ALK）的激活突变。我们对709例神经母细胞瘤肿瘤进行了meta分析，以确定其频率和突变谱与基因组和临床参数的关系，并研究了ALK拷贝数和表达对预后的意义。实验设计：分析了254例新系列神经母细胞瘤中ALK突变的频率和类型、拷贝数增益和表达。来自455个已发表病例的数据被用于进一步深入分析。结果：在709个被调查的肿瘤中，有6.9%存在ALK突变，并且在有利的[国际神经母细胞瘤分期系统（INSS） 1、2和4S；神经母细胞瘤（INSS 3和4；7.5%）较差（P = 0.087）。在R1275和F1174位点发现两个热点突变（分别占突变病例的49%和34.7%）。有趣的是，F1174突变发生在mycn扩增病例中的比例很高（P = 0.001），这种联合发生与特定的不良预后相关，表明两种畸变之间存在积极的合作效应。此外，与R1275Q突变体相比，F1174L突变体具有更高程度的自磷酸化和更强的转化能力。染色体2p的增加，包括ALK位点（91.8%），与ALK表达显著增加相关，这也与较差的生存率相关。结论：ALK突变在所有基因组亚型中发生的频率相同，但F1174L突变在mycn扩增的肿瘤中观察到更高的频率，并且与R1275Q突变相比，其转化能力增强。临床癌症研究；16 (17);4353 - 62。(c) 2010年aacr。
Purpose: Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression.Experimental Design: The frequency and type of ALK mutations, copy number gain, and expression were analyzed in a new series of 254 neuroblastoma tumors. Data from 455 published cases were used for further in-depth analysis.Results: ALK mutations were present in 6.9% of 709 investigated tumors, and mutations were found in similar frequencies in favorable [International Neuroblastoma Staging System (INSS) 1, 2, and 4S; 5.7%] and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P = 0.087). Two hotspot mutations, at positions R1275 and F1174, were observed (49% and 34.7% of the mutated cases, respectively). Interestingly, the F1174 mutations occurred in a high proportion of MYCN-amplified cases (P = 0.001), and this combined occurrence was associated with a particular poor outcome, suggesting a positive cooperative effect between both aberrations. Furthermore, the F1174L mutant was characterized by a higher degree of autophosphorylation and a more potent transforming capacity as compared with the R1275Q mutant. Chromosome 2p gains, including the ALK locus (91.8%), were associated with a significantly increased ALK expression, which was also correlated with poor survival.Conclusions: ALK mutations occur in equal frequencies across all genomic subtypes, but F1174L mutants are observed in a higher frequency of MYCN-amplified tumors and show increased transforming capacity as compared with the R1275Q mutants. Clin Cancer Res; 16(17); 4353-62. (C) 2010 AACR.