Structural and genic characterization of stable genomic regions in breast cancer: Relevance to chemotherapy

Park, Nicole I.; Rogan, Peter K.; Tarnowski, Heather E.; Knoll, Joan H.M.

doi:10.1016/j.molonc.2012.01.001

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Structural and genic characterization of stable genomic regions in breast cancer: Relevance to chemotherapy

Nicole I. Park
- Department of Pathology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
Peter K. Rogan
- Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Department of Computer Science, University of Western Ontario, London, ON, Canada
Heather E. Tarnowski
- Department of Pathology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
Joan H.M. Knoll
- Department of Pathology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Molecular Pathology, Laboratory Medicine Program, London Health Sciences Centre, ON, Canada
- Corresponding author. Department of Pathology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, Rm 4044, 1151 Richmond Street, London, ON, N6A 5C1 Canada. Tel.: +1 519 661 2111x86407.

Received 5 August 2011; received in revised form 28 November 2011; accepted 2 January 2012. published online 24 January 2012.
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Abstract

Background

Cancer genomes accumulate frequent and diverse chromosomal abnormalities as well as gene mutations but must maintain the ability to survive in vivo. We hypothesize that genetic selection acts to maintain tumour survival by preserving copy number of specific genes and genomic regions. Genomic regions and genes that remain unaltered in copy number and expression, respectively, may be essential for maintaining tumour survival.

Methods

We analyzed copy number data of 243 previously reported breast tumours and computationally derived stable copy number regions. To identify genes in stable copy number regions with nominal changes in expression, datasets for tumour and normal samples were compared. Results were replicated by analysis of a series of independent copy number, expression and genomic sequencing studies. A subset of stable regions, including stable paralogous regions, were confirmed by quantitative PCR and fluorescence in situ hybridization (FISH) in 5 breast cancer cell lines. We deduced a comprehensive set of dually stable genes (i.e. maintaining nominal copy number and expression) which were categorized according to pathway and ontology assignments. The stability of genes encoding therapeutic drug targets was also assessed.

Results and Conclusion

Tumour genome analysis revealed 766 unstable (amplified and/or deleted) and 812 stable contiguous genomic regions. Replication analysis of an independent set of 171 breast tumours confirmed copy number stability of 1.3 Gb of the genome. We found that 5804 of these genes were dually stable. The composition of this gene set remained essentially unchanged (<2% reduction) after accounting for commonly mutated breast cancer genes found by sequencing and differential expression. The stable breast cancer genome is enriched for cellular metabolism, regulation of gene expression, DNA packaging (chromatin and nucleosome assembly), and regulation of apoptosis functions. Stable genes participating in multiple essential pathways were consistently found to be targets of chemotherapies. Preservation of stable, essential genes may be related to the effectiveness of certain chemotherapeutic agents that act on multiple gene products in this set.

Graphical abstract

Highlights

► A portion of the genome is stable in a large number of breast tumours. ► The breast cancer genome contains stable paralogous gene-rich sequence families. ► Genes with stable copy number and expression are consistent between independent studies. ► Stable genes define essential biochemical pathways/functions in tumours. ► Stable genes encode targets of systemic breast cancer chemotherapies.

Keywords: Breast cancer, Genomic stability, Chemotherapy, Genetic selection, Array comparative genomic hybridization, Gene expression, Bioinformatics, Fluorescence in situ hybridization