Analysis of chromosome breakpoints in neuroblastoma at sub-kilobase resolution using fine-tiling oligonucleotide array CGH
Analysis of chromosome breakpoints in neuroblastoma at sub-kilobase resolution using fine-tiling oligonucleotide array CGH
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DOI：
10.1002/gcc.20243
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发表时间：
2005-11-01
影响因子：
3.7
通讯作者：
Stallings, RL
中科院分区：
文献类型：
--
作者：
Selzer, RR;Richmond, TA;Stallings, RL
了解恶性肿瘤中复发性染色体不平衡所针对的基因和遗传途径，沿着产生不平衡的分子机制，是癌症生物学中的重要问题。在这份报告中，我们证明了微阵列CGH（oaCGH）分析可以常规地映射染色体不平衡断点;在外显子水平的分辨率，包括单拷贝数基因组改变的不平衡。在这项研究中使用了不同的平铺路径阵列设计：一个全基因组阵列与6 kb的中位数探针间距和精细平铺阵列选择的基因组区域与50或140 bp的中位数探针间距。在这两种阵列形式中，微球探针均为等温设计，并通过基因区和基因间区平铺。对两个神经母细胞瘤细胞系和三个原发性肿瘤的全基因组oaCGH分析导致鉴定出58个染色体断裂点，其产生45个大规模部分染色体不平衡（> 2 Mb）。出乎意料的高比例（34%），这些断点间隔映射到含有节段性重复的区域。此外，检测到88个较小的不平衡区域（< 2 Mb），其中大部分映射到片段重复区域，可能反映了组成拷贝数多态性。在神经母细胞瘤肿瘤和细胞系中表现出的12种复发性异常的染色体断裂点，包括MYCN扩增子边界、3 p缺失、11 q缺失和17 q获得，可以使用高密度精细平铺微阵列映射到大小为50 bp至10 kb的区间。精细平铺oaCGH分析提供了前所未有的分辨率水平，允许详细绘制复发性不平衡染色体异常。这篇文章的补充材料可以在基因，染色体和癌症网站http：//www. interscience.wiley.com/jpages/1045-2257/suppmat/index.html. (c)2005 Wiley-Liss，Inc.
Understanding the genes and genetic pathways targeted by recurrent chromosomal imbalances in malignancy, along with the molecular mechanisms that generate the imbalances, are important problems in cancer biology. In this report, we demonstrate that oligonucleoticle array CGH (oaCGH) analysis can routinely map chromosomal imbalance breakpoints; at exon-level resolution, including imbalances that are single copy number genomic alterations. Different tiling-path array designs were used in this study: a whole-genome array with a 6-kb median probe spacing and fine-tiling arrays for selected genomic regions with either 50- or 140-bp median probe spacing. In both array formats, oligonucleoticle probes were of isothermal design and were tiled through genic and inter-genic regions. Whole-genome oaCGH analysis of two neuroblastoma cell lines and three primary tumors led to the identification of 58 chromosomal breakpoints that generated 45 large-scale partial chromosomal imbalances (> 2 Mb). An unexpectedly high proportion (34%) of these breakpoint intervals mapped to regions containing segmental duplications. In addition, 88 smaller-sized regions (< 2 Mb) of imbalance were detected, the majority of which mapped to segmentally duplicated regions and may reflect constitutional copy number polymorphisms. The chromosomal breakpoints for 12 recurrent abnormalities exhibited in neuroblastoma tumors and cell lines, including MYCN amplicon boundaries, loss of 3p, loss of 11q, and gain of 17q, could be mapped to intervals ranging from 50 bp to 10 kb in size using high-density fine-tiling oligonucleoticle microarrays. Fine-tiling oaCGH analysis provides an unprecedented level of resolution, allowing detailed mapping of recurrent unbalanced chromosomal abnormalities. 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) 2005 Wiley-Liss, Inc.