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 25 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. The comparison of diploid, mismatch repair deficient colorectal carcinomas with aneuploid ones indicates that numerical chromosomal aberrations are 60 times more prevalent in the aneuploid tumors. Abnormalities of the centrosome correlated with chromosomal aneuploidy both in human cancer cell lines and in animal cells deficient for cell cycle regulator genes such as p53 and BRCA1. 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: Structural and functional analysis of abnormal centrosomes and their relationship to chromosome segregation fidelity. Sequential inhibition of p53 and Rb-function with E6 and E7-genes from human papilloma virus 16 and subsequent analyses of chromosomal instability. Microcell mediated chromosome transfer of chromosomes that are frequently gained in colorectal carcinomas into cells derived from normal colorectal epithelium and adenomas followed by cytogenetic analysis and assays for cellular immortalization and transformation. In vitro induction of chromosomal aneuploidy in primary cultures derived from normal murine cells of different organ origin with aneugens followed by cytogenetic analysis and assays for confirmation of cellular immortalization and transformation. Comparison of cells carrying chromosomal aneuploidies with their wildtype parental cells using cDNA microarrays and 2D-gel protein electrophoresis.In two model systems, we have also studied what general consequences recurrent chromosomal aneuploidies exert on gene expression levels in liver metastases of colorectal carcinomas. The results suggest that only a few candidate genes are the target for the acquisition and maintenance of genomic imbalances. However, it became also evident that chromosomal aneuploidies influence average gene expression levels of genes on these aneuploidy chromosomes. The role of such global dysregulation of gene expression patterns with respect to tumorigenesis remains to be elucidated.
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