Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number
Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number
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DOI：
10.1158/0008-5472.can-05-4618
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Maris, John M.
中科院分区：
文献类型：
--
作者：
Wang, Qun;Diskin, Sharon;Maris, John M.
神经母细胞瘤具有显著的临床异质性，其特点是基因组改变与肿瘤行为密切相关。影响神经母细胞瘤生物学并以基因组改变为靶点的特定基因在很大程度上仍不清楚。我们使用基于寡核苷酸的微阵列对101例前瞻性收集的诊断神经母细胞瘤原发肿瘤进行了高度注释的一系列基因表达的量化。用聚合酶链式反应检测预后相关基因1p36、2p24(MYCN)、11q23和17q23的基因组拷贝数状态，分别为26例、20例、40例和38例。此外，在不同实验室检测的72个诊断为神经母细胞瘤的原发肿瘤被用作独立验证集。无监督的分级聚类显示，基因表达与基因组改变和肿瘤行为的临床标志物高度相关。绝大多数具有MYCN扩增和1p36杂合性缺失(LOH)的样本聚集在样本树状图的末端节点上，而具有11q缺失的大多数样本分别聚集在一起，这两者都与拷贝数中性的肿瘤组有很大区别。参与神经发育的基因在更良性的肿瘤中普遍过度表达，而参与RNA加工和细胞增殖的基因在最恶性的病例中高度表达。结合转录学和基因组学数据，我们发现1p和11q的LOH分别与122(61%)和88(27%)定位于1p35-36和11q的基因表达显著降低相关，提示多个基因可能是LOH事件的靶点。在独立的验证数据集中，总共71个1p35-36基因也有差异表达，提供了候选神经母细胞瘤抑制基因的优先列表。综上所述，这些数据与以下假设一致，即神经母细胞瘤转录组是潜在肿瘤生物学的敏感标记，并且该癌症中的染色体缺失事件可能通过改变mRNA剂量而针对多个基因。从这些数据中可以推断出神经母细胞瘤抑制基因的主要候选位置，但所涉及的转录本的潜在多样性对正在进行的基因发现策略具有重要意义。
Neuroblastoma is remarkable for its clinical heterogeneity and is characterized by genomic alterations that are strongly correlated with tumor behavior. The specific genes that influence neuroblastoma biology and are targeted by genomic alterations remain largely unknown. We quantified mRNA expression in a highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors using an oligonucleotide-based microarray. Genomic copy number status at the prognostically relevant loci 1P36, 2p24 (MYCN), 11q23, and 17q23 was determined by PCR and was aberrant in 26, 20, 40, and 38 cases, respectively. In addition, 72 diagnostic neuroblastoma primary tumors assayed in a different laboratory were used as an independent validation set. Unsupervised hierarchical clustering showed that gene expression was highly correlated with genomic alterations and clinical markers of tumor behavior. The vast majority of samples with MYCN amplification and 1p36 loss of heterozygosity (LOH) clustered together on a terminal node of the sample dendrogram, whereas the majority of samples with 11q deletion clustered separately and both of these were largely distinct from the copy number neutral group of tumors. Genes involved in neurodevelopment were broadly overrepresented in the more benign tumors, whereas genes involved in RNA processing and cellular proliferation were highly represented in the most malignant cases. By combining transcriptomic and genomic data, we showed that LOH at 1p and 11q was associated with significantly decreased expression of 122 (61%) and 88 (27%) of the genes mapping to 1p35-36 and all of 11q, respectively, suggesting that multiple genes may be targeted by LOH events. A total of 71 of the 1p35-36 genes were also differentially expressed in the independent validation data set, providing a prioritized list of candidate neuroblastoma suppressor genes. Taken together, these data are consistent with the hypotheses that the neuroblastoma transcriptome is a sensitive marker of underlying tumor biology and that chromosomal deletion events in this cancer likely target multiple genes through alteration in mRNA dosage. Lead positional candidates for neuroblastoma suppressor genes can be inferred from these data, but the potential multiplicity of transcripts involved has significant implications for ongoing gene discovery strategies.