Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations.

Chromosome instability and aneuploidy are hallmarks of cancer, but it is not clear how changes in the chromosomal content of a cell contribute to the malignant phenotype. Previously we have shown that we can readily isolate highly proliferative tumor cells and their revertants from highly invasive tumor cell populations, indicating how phenotypic shifting can contribute to malignant progression. Here we show that chromosome instability and changes in chromosome content occur with phenotypic switching. Further, we show that changes in the copy number of each chromosome quantitatively impose a proportional change in the chromosome transcriptome ratio. This correlation also applies to subchromosomal regions of derivative chromosomes. Importantly, we show that the changes in chromosome content and the transcriptome favor the expression of a large number of genes appropriate for the specific tumor phenotype. We conclude that chromosome instability generates the necessary chromosome diversity in the tumor cell populations and, therefore, the transcriptome diversity to allow for environment-facilitated clonal expansion and clonal evolution of tumor cell populations.