ArrayCGH-based classification of neuroblastoma into genomic subgroups
ArrayCGH-based classification of neuroblastoma into genomic subgroups
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DOI：
10.1002/gcc.20496
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发表时间：
2007-12-01
影响因子：
3.7
通讯作者：
Speleman, Frank
中科院分区：
文献类型：
--
作者：
Michels, Evi;Vandesompele, Jo;Speleman, Frank
高分辨率阵列比较基因组杂交（arrayCGH）分析75原发肿瘤和29细胞系，以进一步了解神经母细胞瘤的遗传异质性和完善基因组亚分类。使用一种新的数据挖掘策略，三个主要和两个次要的基因组亚类划定。83%的肿瘤可以被分配到三个主要的基因组亚类，对应于神经母细胞瘤中三个已知的临床和生物学相关子集。其余亚类代表（1）没有/很少拷贝数改变或畸变非典型模式的肿瘤和（2）11 q 13扩增的肿瘤。个体arrayCGH图谱的检查显示，复发性基因组失衡并不完全与特定亚类相关。特别值得注意的是在I型神经母细胞瘤中通常观察到的数量不平衡的肿瘤，与亚型2A或2B的基因组特征相关。一项对病理学相关基因组改变的研究表明，Iq增益是2A亚型和213亚型肿瘤组内治疗失败的预测标志物。在细胞系中，观察到6 q丢失的高发生率，在6q25.1-6q25.2内具有3.87-5.32 Mb的常见丢失区域。我们的研究清楚地说明了基因组分析在神经母细胞瘤中与肿瘤行为相关的重要性。我们建议在神经母细胞瘤的遗传学检查中应该包括全基因组拷贝数改变的评估。需要对大型肿瘤系列进行进一步的多中心研究，以便结合其他特征（如诊断时的年龄、肿瘤分期和基因表达特征）改善治疗分层。
High-resolution array comparative genomic hybridization (arrayCGH) profiling was performed on 75 primary tumors and 29 cell lines to gain further insight into the genetic heterogeneity of neuroblastoma and to refine genomic subclassification. Using a novel data-mining strategy, three major and two minor genomic subclasses were delineated. Eighty-three percent of tumors could be assigned to the three major genomic subclasses, corresponding to the three known clinically and biologically relevant subsets in neuroblastoma. The remaining subclasses represented (1) tumors with no/few copy number alterations or an atypical pattern of aberrations and (2) tumors with 11 q 13 amplification. Inspection of individual arrayCGH profiles showed that recurrent genomic imbalances were not exclusively associated with a specific subclass. Of particular notice were tumors with numerical imbalances typically observed in subtype I neuroblastoma, in association with genomic features of subtype 2A or 2B. A search for prognostically relevant genomic alterations disclosed I q gain as a predictive marker for therapy failure within the group of subtype 2A and 213 tumors. In cell lines, a high incidence of 6q loss was observed, with a 3.87-5.32 Mb region of common loss within 6q25.1-6q25.2. Our study clearly illustrates the importance of genomic profiling in relation to tumor behavior in neuroblastoma. We propose that genome-wide assessment of copy number alterations should ideally be included in the genetic workup of neuroblastoma. Further multicentric studies on large tumor series are warranted in order to improve therapeutic stratification in conjunction with other features such as age at diagnosis, tumor stage, and gene expression signatures.