Upender Madhvi B, Habermann Jens K, McShane Lisa M, Korn Edward L, Barrett J Carl, Difilippantonio Michael J, Ried Thomas
Genetics Branch and Laboratory for Biosystems and Cancer, Center for Cancer Research and Biometric Research Branch, National Cancer Institute/NIH, Bethesda, Maryland 20892-8010, USA.
Cancer Res. 2004 Oct 1;64(19):6941-9. doi: 10.1158/0008-5472.CAN-04-0474.
Chromosomal aneuploidies are observed in essentially all sporadic carcinomas. These aneuploidies result in tumor-specific patterns of genomic imbalances that are acquired early during tumorigenesis, continuously selected for and faithfully maintained in cancer cells. Although the paradigm of translocation induced oncogene activation in hematologic malignancies is firmly established, it is not known how genomic imbalances affect chromosome-specific gene expression patterns in particular and how chromosomal aneuploidy dysregulates the genetic equilibrium of cells in general. To model specific chromosomal aneuploidies in cancer cells and dissect the immediate consequences of genomic imbalances on the transcriptome, we generated artificial trisomies in a karyotypically stable diploid yet mismatch repair-deficient, colorectal cancer cell line and in telomerase immortalized, cytogenetically normal human breast epithelial cells using microcell-mediated chromosome transfer. The global consequences on gene expression levels were analyzed using cDNA arrays. Our results show that regardless of chromosome or cell type, chromosomal trisomies result in a significant increase in the average transcriptional activity of the trisomic chromosome. This increase affects the expression of numerous genes on other chromosomes as well. We therefore postulate that the genomic imbalances observed in cancer cells exert their effect through a complex pattern of transcriptional dysregulation.
在几乎所有散发性癌中均观察到染色体非整倍体。这些非整倍体导致基因组失衡的肿瘤特异性模式，这些模式在肿瘤发生早期获得，在癌细胞中持续被选择并稳定维持。虽然在血液系统恶性肿瘤中，易位诱导癌基因激活的模式已被牢固确立，但尚不清楚基因组失衡如何具体影响特定染色体的基因表达模式，以及染色体非整倍体如何总体上失调细胞的遗传平衡。为了在癌细胞中模拟特定的染色体非整倍体，并剖析基因组失衡对转录组产生的直接后果，我们使用微细胞介导的染色体转移，在核型稳定的二倍体但错配修复缺陷的结肠癌细胞系以及端粒酶永生化、细胞遗传学正常的人乳腺上皮细胞中产生了人工三体。使用cDNA阵列分析了对基因表达水平的整体影响。我们的结果表明，无论染色体或细胞类型如何，染色体三体均导致三体染色体的平均转录活性显著增加。这种增加也影响其他染色体上众多基因的表达。因此，我们推测在癌细胞中观察到的基因组失衡通过复杂的转录失调模式发挥作用。
