Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression
Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression
复制标题
DOI：
10.1002/gcc.20477
复制
发表时间：
2007-10-01
影响因子：
3.7
通讯作者：
Maris, John M.
中科院分区：
文献类型：
--
作者：
Mosse, Yael P.;Diskin, Sharon J.;Maris, John M.
神经母细胞瘤是一种异质性肿瘤，已成为体细胞获得性基因组畸变临床应用的范例。 DNA 拷贝数改变 (CNA) 目前用于预测预后，包括 MYCN 扩增以及染色体带 1p36 和 11q23 的缺失。我们预测，对神经母细胞瘤中 DNA 畸变进行全基因组评估将提供对临床表型的更精确估计，并可用于预测结果。我们在定制的基于高分辨率 BAC 阵列的 CGH 平台上测量了一组具有代表性的 82 个诊断肿瘤中的 CNA，并补充了 1p36、2p24、3p21-22、11q14-24 和 16p12-13 的其他克隆，并将这些数据与 RNA 表达数据整合。我们使用无偏统计方法来定义一组像差的最小公共区域 (MCR)。无监督的层次聚类确定了四个不同的基因组亚类。首先，具有临床良性表型的肿瘤子集主要表现出全染色体的获得和丢失。其次，MYCN 扩增的肿瘤具有 1p 缺失和 17q 增益的独特基因组特征，但几乎没有其他重排。第三，具有侵袭性临床表型但没有 MYCN 扩增的肿瘤显示出多种结构重排。最值得注意的是 3p、4p 和 11q 的缺失以及 1q、2p、12q 和 17q 的增加。最后，有一类肿瘤具有侵袭性临床表型，并且没有可检测到的 DNA CNA。基因组亚群与患者结果高度相关，并且个体 MCR 在多变量模型中仍然具有预后意义。 DNA 特征模式在神经母细胞瘤诊断样本中嵌入了重要的预后信息，并且可以识别候选的癌症相关基因。本文的补充材料可以在基因、染色体和癌症网站 http://www.interscience 上找到。 wiley.com/jpages/1045-2257/supmat/index.html。 (c) 2007 年 Wiley-Liss, Inc.
Neuroblastoma is a heterogeneous neoplasm that has served as a paradigm for the clinical utility of somatically acquired genomic aberrations. DNA copy number alterations (CNA) are currently used to predict prognosis, including MYCN amplification and deletions at chromosome bands 1p36 and 11q23. We predicted that genome-wide assessment of DNA aberrations in neuroblastoma tumors would provide a more precise estimation of clinical phenotype, and could be used to predict outcome. We measured CNAs in a representative set of 82 diagnostic tumors on a customized high-resolution BAC array-based CGH platform supplemented with additional clones across 1p36, 2p24, 3p21-22, 11q14-24, and 16p12-13, and integrated these data with RNA expression data. We used an unbiased statistical method to define a set of minimal common regions (MCRs) of aberration. Unsupervised hierarchical clustering identified four distinct genomic subclasses. First, a subset of tumors with a clinically benign phenotype showed predominantly whole chromosome gains and losses. Second, tumors with MYCN amplification had a unique genomic signature of 1p deletion and 17q gain, but few other rearrangements. Third, tumors with an aggressive clinical phenotype without MYCN amplification, showed multiple structural rearrangements. Most notable were deletions of 3p, 4p, and 11q and gain of 1q, 2p, 12q, and 17q. Lastly, there was a subset of tumors with an aggressive clinical phenotype and no detectable DNA CNAs. The genomic subsets were highly correlated with patient outcome, and individual MCRs remained prognostic in a multivariable model. DNA signature patterns embed important prognostic information in diagnostic neuroblastoma samples, and can identify candidate cancer-related genes. Supplementary material for this article can be found on the Genes, Chromosomes, and Cancer website at http://www.interscience. wiley.com/jpages/1045-2257/suppmat/index.html. (c) 2007 Wiley-Liss, Inc.