Abstract
BackgroundTumor 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).MethodsWe 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.ResultsHere 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.ConclusionsOur 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.
Highlights
Tumor development is known to be a stepwise process involving dynamic changes that affect cellular integrity and cellular behavior
Copy number alterations were calculated from signal intensities detected by high-throughput single nucleotide polymorphism (SNP) microarrays
In this work we study the copy number alterations (CNA) of a four stage tumorigenesis model
Summary
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. Research has been focused on discovering gene expression profiles, alterations in oncogenes or tumor-suppressors, and genetic mutations; but since tumorigenesis is a complex multistep process, the transformation of a normal cell into a malignant tumor is. Agam et al [17] compared the CNAs found in the four mentioned studies with their own data and found significant differences They show that 1.3% to 88.7% of the detected deletions and 2.1% to 100% of the gains are replicated from one study to the following ones. The study of Jornsten et al [20] used a global model of CNA-driven transcription to model mRNA expressions with the help of CNAs
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