Chromosome transfer induced aneuploidy results in complex dysregulation of the cellular transcriptome in immortalized and cancer cells - PubMed (original) (raw)

Chromosome transfer induced aneuploidy results in complex dysregulation of the cellular transcriptome in immortalized and cancer cells

Madhvi B Upender et al. Cancer Res. 2004.

Abstract

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.

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Figures

Fig. 1

Fig. 1

Characterization of chromosome transfer clones. A, representative interphase/metaphase FISH experiment with 4′,6-diamidino-2-phenylindole counterstained DNA and centromere probes for chromosomes 3 (yellow) and 7 (red) in the DLD1 + 7 clone. B, population of cells within each clone containing two (yellow), three (red), or more than three (blue) copies of the introduced chromosome. C, representative karyotype from a SKY analysis of the parental cell line, DLD1. D, a spectral karyotype from the DLD1 + 3 clone clearly showing three copies of chromosome 3 and maintenance of the diploid DLD1 background.

Fig. 2

Fig. 2

Global gene expression profiles. Each scatterplot displays all genes and their corresponding normalized expression ratio values along the length of each chromosome. Values in open light blue circles and open light orange circles represent ratio values between 0.5 and 2.0. Dark blue dots represent expression ratios ≥ 2.0 and dark orange dots are ratios ≤ 0.5. The X axis shows the starting bp location of each gene.

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