title: Micro-scale genomic DNA copy number aberrations as another means of mutagenesis in breast cancer.
abstract: BACKGROUND
  In breast cancer, the basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. There is evidence that this genomic instability extends to smaller scale genomic aberrations, as shown by a previously described micro-deletion event in the PTEN gene in the Basal-like SUM149 breast cancer cell line.
  
  
  METHODS
  We sought to identify if small regions of genomic DNA copy number changes exist by using a high density, gene-centric Comparative Genomic Hybridizations (CGH) array on cell lines and primary tumors. A custom tiling array for CGH (244,000 probes, 200 bp tiling resolution) was created to identify small regions of genomic change, which was focused on previously identified basal-like-specific, and general cancer genes. Tumor genomic DNA from 94 patients and 2 breast cancer cell lines was labeled and hybridized to these arrays. Aberrations were called using SWITCHdna and the smallest 25% of SWITCHdna-defined genomic segments were called micro-aberrations (<64 contiguous probes, ~ 15 kb).
  
  
  RESULTS
  Our data showed that primary tumor breast cancer genomes frequently contained many small-scale copy number gains and losses, termed micro-aberrations, most of which are undetectable using typical-density genome-wide aCGH arrays. The basal-like subtype exhibited the highest incidence of these events. These micro-aberrations sometimes altered expression of the involved gene. We confirmed the presence of the PTEN micro-amplification in SUM149 and by mRNA-seq showed that this resulted in loss of expression of all exons downstream of this event. Micro-aberrations disproportionately affected the 5' regions of the affected genes, including the promoter region, and high frequency of micro-aberrations was associated with poor survival.
  
  
  CONCLUSIONS
  Using a high-probe-density, gene-centric aCGH microarray, we present evidence of small-scale genomic aberrations that can contribute to gene inactivation. These events may contribute to tumor formation through mechanisms not detected using conventional DNA copy number analyses.
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Hann-Hsiang
authors.initials: HH
authors.lastname: Chao
authors.forename: Xiaping
authors.initials: X
authors.lastname: He
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor