Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Genes Chromosomes Cancer. 2009 Nov;48(11):1002-17. doi: 10.1002/gcc.20699.
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.
为了评估结直肠癌（CRC）中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）和基于阵列的全基因组基因表达谱分析相结合的方法，对 31 个原发性肿瘤和 15 个已建立的细胞系进行了研究。重要的是，aCGH 显示，原发性肿瘤的基因组图谱在细胞系中得到了重现。我们揭示了结直肠癌细胞系中染色体断裂点主要位于拷贝数变异（CNV）的位置，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 157 个基因定位于高水平拷贝数变化区域，这些基因在所有样本中均受到明显的转录失调影响，这表明这些基因在 CRC 中发挥了功能作用。8q24 处的基因组扩增是最常见的事件，导致 MYC 和 FAM84B 的过度表达。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。仅鉴定出 36 个基因，其在断裂点附近的定位可以解释它们观察到的失调表达，这表明 CRC 中转录失调的主要机制是染色体畸变导致的基因组拷贝数变化。
