Integrative genomics reveals mechanisms of copy number alterations responsible for transcriptional deregulation in colorectal cancer.
Integrative genomics reveals mechanisms of copy number alterations responsible for transcriptional deregulation in colorectal cancer.
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DOI：
10.1002/gcc.20699
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发表时间：
2009-11
期刊：
影响因子：
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通讯作者：
Difilippantonio MJ
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文献类型：
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作者：
Camps J;Nguyen QT;Padilla-Nash HM;Knutsen T;McNeil NE;Wangsa D;Hummon AB;Grade M;Ried T;Difilippantonio MJ
为了评估结直肠癌（CRC）染色体畸变的机制和后果，我们使用了光谱核型分析，阵列比较基因组杂交（aCGH），和基于阵列的全球基因表达谱的31原发癌和15个已建立的细胞系的组合。重要的是，aCGH显示原发性肿瘤的基因组谱在细胞系中重现。我们揭示了CRC细胞系中拷贝数变异（CNVs）位点处染色体断裂点的优势，这是癌症中DNA断裂的一种新机制。基因表达和aCGH的整合导致鉴定出定位于高水平拷贝数变化内的157个基因，其转录失调在所有样品中均受到显著影响，从而表明这些基因在CRC中发挥功能性作用。8q24的基因组扩增是最常发生的事件，并导致MYC和FAM84B的过表达。拷贝数依赖性基因表达导致已知癌症基因如APC、FGFR2和ERBB2的失调。仅鉴定了36个基因，其在断点附近的定位可以解释其观察到的表达失调，这表明CRC中转录失调的主要机制是染色体畸变引起的基因组拷贝数变化。
To evaluate the mechanisms and consequences of chromosomal aberrations in colorectal cancer (CRC), we used a combination of spectral karyotyping, array comparative genomic hybridization (aCGH), and array-based global gene expression profiling on 31 primary carcinomas and 15 established cell lines. Importantly, aCGH showed that the genomic profiles of primary tumors are recapitulated in the cell lines. We revealed a preponderance of chromosome breakpoints at sites of copy number variants (CNVs) in the CRC cell lines, a novel mechanism of DNA breakage in cancer. The integration of gene expression and aCGH led to the identification of 157 genes localized within high-level copy number changes whose transcriptional deregulation was significantly affected across all of the samples, thereby suggesting that these genes play a functional role in CRC. Genomic amplification at 8q24 was the most recurrent event and led to the overexpression of MYC and FAM84B. Copy number dependent gene expression resulted in deregulation of known cancer genes such as APC, FGFR2, and ERBB2. The identification of only 36 genes whose localization near a breakpoint could account for their observed deregulated expression demonstrates that the major mechanism for transcriptional deregulation in CRC is genomic copy number changes resulting from chromosomal aberrations.