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

• Published in: Molecular oncology 2012-06, Vol.6 (3), p.347-359
• Main Authors: Park, Nicole I., Rogan, Peter K., Tarnowski, Heather E., Knoll, Joan H.M.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Apoptosis; Array comparative genomic hybridization; Bioinformatics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Chemotherapy; Chromatin remodeling; Chromosome aberrations; Chromosomes; Copy number; Datasets; DNA methylation; DNA sequencing; Female; Fluorescence in situ hybridization; Gene expression; Gene regulation; Genetic diversity; Genetic selection; Genome, Human - genetics; Genomes; Genomic analysis; Genomic stability; Humans; In Situ Hybridization, Fluorescence; Mutation; Ontology; Point mutation; Polymerase Chain Reaction; Proteins; Therapeutic targets; Tumor cell lines; Tumors
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2012.01.001

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. 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. 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 (