SNP microarray analyses reveal copy number alterations and progressive genome reorganization during tumor development...

Tumor development is known to be a stepwise process involving dynamic changes that affect cellular integrity and cellular behavior. This complex interaction between genomic organization and gene, as well as protein expression is not yet fully understood. Tumor characterization by gene expression analyses is not sufficient, since expression levels are only available as a snapshot of the cell status. So far, research has mainly focused on gene expression profiling or alterations in oncogenes, even though DNA microarray platforms would allow for high-throughput analyses of copy number alterations (CNAs).

We analyzed DNA from mouse mammary gland epithelial cells using the Affymetrix Mouse Diversity Genotyping array (MOUSEDIVm520650) and calculated the CNAs. Segmental copy number alterations were computed based on the probeset CNAs using the circular binary segmentation algorithm. Motif search was performed in breakpoint regions (inter-segment regions) with the MEME suite to identify common motif sequences.

Here we present a four stage mouse model addressing copy number alterations in tumorigenesis. No considerable changes in CNA were identified for non-transgenic mice, but a stepwise increase in CNA was found during tumor development. The segmental copy number alteration revealed informative chromosomal fragmentation patterns. In inter-segment regions (hypothetical breakpoint sides) unique motifs were found.

Our analyses suggest genome reorganization as a stepwise process that involves amplifications and deletions of chromosomal regions. We conclude from distinctive fragmentation patterns that conserved as well as individual breakpoints exist which promote tumorigenesis.