The review of CGH analyses performed in our laboratory has revealed that the acquisition of whole chromosomes or chromosome arm gains and losses is a frequent event, particularly at early stages of carcinogenesis. The comparison of come 50 cell lines established from solid tumors by SKY and CGH has provided compelling evidence that the vast majority of epithelial cancers have either numerical or structural chromosomal aberrations resulting in genomic imbalances. All these results taken together support the notion that chromosomal aneuploidy is a major theme in epithelial cancers. In order to elucidate mechanisms leading to aneuploidy, to establish the functional relevance of chromosomal aneuploidy, and to identify whether aneuploidy is a cause or a consequence of genetic changes in solid tumors, we have focused on the following projects:2.1Chromosome transfer induced aneuploidy results in complex dysregulation of the cellular transcriptome in immortalized and cancer cellsChromosomal aneuploidies are observed in essentially all sporadic carcinomas. Aneuploidy results in tumor specific patterns of genomic imbalances that are acquired early during tumorigenesis, continuously selected for and faithfully maintained in cancer cells. While the paradigm of translocation induced oncogene activation in hematological malignancies is firmly established, it is not known how chromosomal aneuploidy deregulates the genetic equilibrium of cells in general, and how these genomic imbalances affect chromosome specific gene expression patterns in particular. In order 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. Global gene expression levels were analyzed using cDNA arrays. We wished to determine what affect chromosome copy number increases have on the average expression levels of genes residing on the trisomic chromosomes as well as how these particular aneuploidies affect the regulation of individual genes throughout the entire genome. 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 deregulation. 2.2Aneuploidy-Dependant Massive Deregulation of the Cellular Transcriptome in Human Rectal CarcinomasIn order to identify genetic alterations underlying rectal carcinogenesis, we used global gene expression profiling of a series of 17 locally advanced rectal adenocarcinomas and 20 normal rectal mucosa biopsies on oligonucleotide arrays. A total of 351 genes were differentially expressed (p less than 1.0e-7) between normal rectal mucosa and rectal carcinomas, 77 genes had a greater than five-fold difference, and 85 genes always had at least a two-fold change in all of the matched samples. 12 genes satisfied all three of these criteria. Altered expression of genes such as PTGS2 (COX2), WNT1, TGFB1, VEGF and MYC were confirmed, while our data for other genes like PPARD and LEF1 were inconsistent with previous reports. In addition, we found dysregulated expression of many genes whose involvement in rectal carcinogenesis has not been reported. By mapping the genomic imbalances in the tumors using comparative genomic hybridization, we could show that DNA copy number gains of recurrently aneuploid chromosome arms 7p, 8q, 13q, 18q, 20p and 20q correlated significantly with their average chromosome arm expression profile.

National Institute of Health (NIH)
Division of Clinical Sciences - NCI (NCI)
Intramural Research (Z01)
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Clinical Sciences
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Mazumdar, Manjari; Lee, Ji-Hyeon; Sengupta, Kundan et al. (2006) Tumor formation via loss of a molecular motor protein. Curr Biol 16:1559-64
Jang, Wonhee; Yonescu, Raluca; Knutsen, Turid et al. (2006) Linking the human cytogenetic map with nucleotide sequence: the CCAP clone set. Cancer Genet Cytogenet 168:89-97
Miura, Masako; Miura, Yasuo; Padilla-Nash, Hesed M et al. (2006) Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation. Stem Cells 24:1095-103
Focarelli, Maria Luisa; Montagna, Cristina; Colombo, Roberto et al. (2006) SMC1 inhibition results in FRA3B expression but has no effect on its delayed replication. Mutat Res 595:23-8
Grade, Marian; Ghadimi, B Michael; Varma, Sudhir et al. (2006) Aneuploidy-dependent massive deregulation of the cellular transcriptome and apparent divergence of the Wnt/beta-catenin signaling pathway in human rectal carcinomas. Cancer Res 66:267-82
Rao, V Koneti; Knutsen, Turid; Ried, Thomas et al. (2005) The extent of chromosomal aberrations induced by chemotherapy in non-human primates depends on the schedule of administration. Mutat Res 583:105-19
Musio, Antonio; Montagna, Cristina; Mariani, Tullio et al. (2005) SMC1 involvement in fragile site expression. Hum Mol Genet 14:525-33
Desper, Richard; Difilippantonio, Michael J; Ried, Thomas et al. (2005) A comprehensive continuous-time model for the appearance of CGH signal due to chromosomal missegregations during mitosis. Math Biosci 197:67-87
Knutsen, Turid; Gobu, Vasuki; Knaus, Rodger et al. (2005) The interactive online SKY/M-FISH & CGH database and the Entrez cancer chromosomes search database: linkage of chromosomal aberrations with the genome sequence. Genes Chromosomes Cancer 44:52-64
Schaeffer, Anthony J; Nguyen, Marie; Liem, Amy et al. (2004) E6 and E7 oncoproteins induce distinct patterns of chromosomal aneuploidy in skin tumors from transgenic mice. Cancer Res 64:538-46

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