The parallel analysis of a large set (n=150) of colorectal cancer samples using both CGH and expression profiling allowed establishing a direct correlation of chromosomal copy number changes and chromosome specific average gene expression levels for chromosomes 7, 13, 17, 18, and 20 (p<0.01). We were able to establish a relationship between specific genomic imbalances and alterations of global transcriptional activity. In conclusion, increasing genomic instability and a recurrent pattern of chromosomal aberrations as well as distinct gene- and protein expression patterns correlate with distinct stages of colorectal cancer progression. Chromosomal aneuploidies exert a direct effect on average expression levels of the genes residing on the aneuploid chromosomes thereby contributing to a massive deregulation of the cellular transcriptome. This aneuploidy-dependent transcriptional deregulation is not specific for colon cancer, as we have observed a similar phenomenon in primary breast cancer as well. Chromosomal aneuploidy is a defining feature of the vast majority of carcinomas. In non-hereditary forms of colon cancer, additional copies of chromosomes 7, 13 and 20 are not only observed in early pre-dysplastic lesions, but are faithfully maintained throughout progression to metastasis. It has been established that chromosomes assume a well conserved 3-dimensional positioning within the interphase nucleus. An increase in chromosome copy number has also been shown to correlate with an overall increased expression of genes residing on that chromosome. We are therefore performing 3-dimensional fluorescence in situ hybridization (3D-FISH) on cell lines containing artificially derived trisomies to determine if this increased expression required the aneuploid chromosome to adopt the same nuclear position as its endogenous homologues. Our results demonstrate that endogenous chromosome 7 and 18 territories are peripheral in position, while chromosome 19 territories are centrally localized. Remarkably, the artificially introduced trisomic chromosomes are positioned identically to their endogenous counterparts in the colon cancer cell line DLD-1. Our data is therefore consistent with the idea that inherent to each chromosome is a zip code that determines its nuclear localization. Whether localization is merely a reflection of gene density or is somehow the result of the transcriptional activation of a chromosome remains to be determined. Our data is therefore consistent with the model that each chromosome has an associated zip code (possibly gene density) that determines its nuclear localization. Whether the nuclear localization determines or is determined by the transcriptional activity of resident genes has yet to be ascertained.
