Micro-scale genomic copy number aberrations as another means of mutagenesis in breast cancer

ABSTRACT: Introduction: In breast cancers, 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 well, as shown by a previously described micro-event in the PTEN gene in the Basal-like SUM149 breast cancer cell line. Methods: We sought to identify if small regions of genomic change exist by using a high density, gene centric Comparative Genomic Hybridizations (CGH) array on both cell lines and primary tumors. A custom Agilent tiling array for CGH (244,000 probes, 200bp tiling resolution) was created to identify small regions of genomic change and 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 being called micro-aberrations (<64 contiguous probes, ~ <15kb). Results: Our data showed that primary tumor breast cancer genomes frequently contained areas of small-scale copy number gains and losses, termed micro-aberrations, which are undetectable using lower-density genome-wide platforms. The basal-like subtype exhibited the highest incidence of these events. These micro-aberrations sometimes altered expression of the involved gene as suggested by data from microarray and mRNA-seq studies. 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 a high frequency of micro-aberrations was associated with poor survival outcomes. Conclusion: Using a high probe density, gene-centric aCGH microarray, we present evidence of small-scale genomic aberrations that contribute to gene inactivation, and thus, genomic instability and tumor formation through a mechanism not detected using conventional copy number analyses. reference x sample

ORGANISM(S): Homo sapiens

SUBMITTER: Charles Perou 

PROVIDER: E-GEOD-36889 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress