Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors
Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors
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DOI：
10.1073/pnas.162471999
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发表时间：
2002-10-01
影响因子：
11.1
通讯作者：
Brown, PO
中科院分区：
文献类型：
--
作者：
Pollack, JR;Sorlie, T;Brown, PO
基因组DNA拷贝数改变是人类癌症发生和发展的关键遗传事件。在这里，我们报告了一个全基因组微阵列比较基因组杂交（阵列CGH）分析的DNA拷贝数变异的一系列原发性人类乳腺肿瘤。我们在44个主要的晚期原发性乳腺肿瘤和10个乳腺癌细胞系中分析了6，691个映射的人类基因的DNA拷贝数变化。虽然DNA扩增和缺失的整体模式证实了以前的细胞遗传学研究，高分辨率（基因-基因）扩增子边界的映射和扩增子形状的定量分析提供了显着的改善候选癌基因的本地化。mRNA水平的平行微阵列测量揭示了基因拷贝数的变化对肿瘤细胞中基因表达变化的显著程度。具体地说，我们发现62%的高度扩增基因表现出中度或高度升高的表达，DNA拷贝数影响基因表达的范围很广，（缺失，低、中和高水平扩增），平均而言，DNA拷贝数的2倍变化与mRNA水平的相应1.5倍变化相关，并且总体而言，乳腺肿瘤中基因表达的所有变异中至少有12%直接归因于基因拷贝数的潜在变异。这些发现提供了证据，表明广泛的DNA拷贝数改变可以直接导致基因表达的全球失调，这可能有助于癌症的发展或进展。
Genomic DNA copy number alterations are key genetic events in the development and progression of human cancers. Here we report a genome-wide microarray comparative genomic hybridization (array CGH) analysis of DNA copy number variation in a series of primary human breast tumors. We have profiled DNA copy number alteration across 6,691 mapped human genes, in 44 predominantly advanced, primary breast tumors and 10 breast cancer cell lines. While the overall patterns of DNA amplification and deletion corroborate previous cytogenetic studies, the high-resolution (gene-by-gene) mapping of amplicon boundaries and the quantitative analysis of amplicon shape provide significant improvement in the localization of candidate oncogenes. Parallel microarray measurements of mRNA levels reveal the remarkable degree to which variation in gene copy number contributes to variation in gene expression in tumor cells. Specifically, we find that 62% of highly amplified genes show moderately or highly elevated expression, that DNA copy number influences gene expression across a wide range of DNA copy number alterations (deletion, low-, mid- and high-level amplification), that on average, a 2-fold change in DNA copy number is associated with a corresponding 1.5-fold change in mRNA levels, and that overall, at least 12% of all the variation in gene expression among the breast tumors is directly attributable to underlying variation in gene copy number. These findings provide evidence that widespread DNA copy number alteration can lead directly to global deregulation of gene expression, which may contribute to the development or progression of cancer.